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Special Collection on Lung Cancer

Worldwide, the two most common cancers are lung and breast cancer and, according to the CDC, smoking cigarettes is linked to 80-90% of lung cancer deaths in the United States.

Some symptoms of lung cancer:
  • Pain in chest or ribs
  • Frequent respiratory infections, shortness of breath, wheezing
  • Fatigue or loss of appetite
In non-smokers, lung cancer can be caused by exposure to radon, secondhand smoke, air pollution, asbestos, diesel exhaust, and other chemicals and factors. Numerous research studies about lung cancer are currently underway, and we hope this Special Collection will set future research in motion to discover more causes and treatments for this disease.

Lung cancer is treatable if detected early by a surgical oncologist—a doctor who is trained in administering various treatments for different cancer types.

What is Lung Cancer?

Worldwide, the two most common cancers are lung and breast cancer and, according to the CDC, smoking cigarettes is linked to 80-90% of lung cancer deaths in the United States.

Some symptoms of lung cancer:
  • Pain in chest or ribs
  • Frequent respiratory infections, shortness of breath, wheezing
  • Fatigue or loss of appetite
In non-smokers, lung cancer can be caused by exposure to radon, secondhand smoke, air pollution, asbestos, diesel exhaust, and other chemicals and factors. Numerous research studies about lung cancer are currently underway, and we hope this Special Collection will set future research in motion to discover more causes and treatments for this disease.

Lung cancer is treatable if detected early by a surgical oncologist—a doctor who is trained in administering various treatments for different cancer types.

Physician type:

Surgical oncologist


ANZSRC Categories:

1112 Oncology and Carcinogenesis


RCDC Category: Lung Cancer
Keywords: lung, cancer, smoking, cigarettes, negative, trastuzumab, expression, resistance, factor, prognostic, metastasis

Table of Contents

Reviews

Clinical strategies for acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small-cell lung cancer patients

DOI: 10.18632/oncotarget.19925

Lijun Dong, Dan Lei and Haijun Zhang _

Abstract | PDF | HTML | Altmetric Report

Epidermal growth factor receptor (EGFR) mutations (EGFRm+) occur in 10–35% of non-small-cell lung cancer (NSCLC) cases and confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs are standard treatments for NSCLC patients harboring EGFR exon 19 deletions or exon 21 L858R point mutations. Despite initial benefit, most patients develop drug resistance, posing a challenge to oncologists. The secondary T790M point mutation in EGFR exon 20 contributes to approximately 60% of resistance cases. Optimum strategies for overcoming acquired EGFR TKI resistance are not clearly defined, although current common practice is to switch to platinum-based chemotherapy following resistance onset. While the second-generation EGFR TKIs, including afatinib, dacomitinib, and neratinib, exhibit promising preclinical activity against T790M mutants, dose-limiting toxicities in patients have limited clinical success. However, third generation EGFR TKIs appear able to overcome this mutation. Other treatment options aimed at EGFR TKI resistance include use of an EGFR TKI beyond progression, and chemotherapy plus an EGFR TKI. This review focuses on improved anticancer agents and therapy options for NSCLC patients with acquired EGFR TKI resistance.

Clinical Research Papers

Phase III study of cisplatin with pemtrexed or vinorelbine plus concurrent late course accelerated hyperfractionated radiotherapy in patients with unresectable stage III non-small cell lung cancer

DOI: 10.18632/oncotarget.6871

Qian Zhao, Zhongtang Wang, Wei Huang, Qiang Wang, Shuzeng Yu, Tao Zhou, Dan Han, Zhenying Wu, Heyi Gong, Hongfu Sun, Jian Zhang, Yumei Wei, Hongsheng Li, Zicheng Zhang, Haiqun Lin and Baosheng Li _

Abstract | PDF | HTML | Altmetric Report

Our aim was to evaluate the efficacy and safety of cisplatin with pemtrexed or vinorelbine and concurrent late course accelerated hyperfractionated radiotherapy (LCAHRT). Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to two regimens. The experimental (PP) arm included cisplatin, pemtrexed and concurrent LCAHRT based on bilateral lung V20 = 33%. The control (NP) arm used cisplatin, vinorelbine with the same radiotherapy protocol. The primary endpoint was overall survival. Median survival times were 26.0 months (95% CI 23.2 to 28.7 months) and 28.5 months (95% CI 17.1 to 39.9 months) for the NP and PP arms, respectively (P = 0.26). Median progression-free survival was 12.5 months and 17.5 months in the NP and PP arms (P = 0.07). In both arms of the study, there were no differences in overall survival between patients with squamous and nonsquamous NSCLC. The incidences of grade 3 or 4 toxicity were higher in NP than PP arm. With concurrent LCAHRT, pemetrexed/cisplatin was equally as efficacious as vinorelbine/cisplatin, but showed a more favorable toxicity profile.

Research Papers

Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

DOI: 10.18632/oncotarget.10581

Ai N.H. Phan, Tuyen N.M. Hua, Min-Kyu Kim, Vu T.A. Vo, Jong-Whan Choi, Hyun-Won Kim, Jin Kyung Rho, Ki Woo Kim and Yangsik Jeong _

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have clinically benefited to lung cancer patients harboring a subset of activating EGFR mutations. However, even with the remarkable therapeutic response at the initial TKI treatment, most lung cancer patients eventually have relapsed aggressive tumors due to acquired resistance to the TKIs. Here, we report that 3, 4, 5-trihydroxybenzoic acid or gallic acid (GA), a natural polyphenolic compound, shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC). Using both in vitro growth assay and in vivo xenograft animal model, we demonstrated tumor suppressive effect of GA was more selective for the TKI-resistant cancer compared to the TKI-sensitive one. Mechanistically, GA treatment inhibited Src-Stat3-mediated signaling and decreased the expression of Stat3-regulated tumor promoting genes, subsequently inducing apoptosis and cell cycle arrest in the TKI-resistant lung cancer but not in the TKI-sensitive one. Consistent with the in vitro results, in vivo xenograft experiments showed the TKI-resistant tumor-selective growth inhibition and suppression of Src-Stat3-dependent signaling in the GA-treated tumors isolated from the xenograft model. This finding identified an importance of Src-Stat3 signaling cascade in GA-mediated tumor-suppression activity and, more importantly, provides a novel therapeutic insight of GA for advanced TKI-resistant lung cancer.

Research Papers

Targeting the cancer stem cell marker, aldehyde dehydrogenase 1, to circumvent cisplatin resistance in NSCLC

DOI: 10.18632/oncotarget.19881

Lauren MacDonagh, Michael F. Gallagher, Brendan Ffrench, Claudia Gasch, Eamon Breen, Steven G. Gray, Siobhan Nicholson, Niamh Leonard, Ronan Ryan, Vincent Young, John J. O’Leary, Sinead Cuffe, Stephen P. Finn, Kenneth J. O’Byrne and Martin P. Barr _

Abstract | PDF | HTML | Altmetric Report

Non-small cell lung cancer (NSCLC) accounts for a large proportion of cancer deaths and is characterized by low treatment response rates and poor overall prognosis. In the absence of specific treatable mutations, cisplatin-based chemotherapy plays an important role in the treatment of this disease. Unfortunately, the development of resistance has become a major therapeutic challenge in the use of this cytotoxic drug. Elucidating the mechanisms underlying this resistance phenotype, may result in the development of novel agents that enhance sensitivity to cisplatin in lung cancer patients. In this study, targeting the cancer stem cell activity of aldehyde dehydrogenase 1 (ALDH1) was investigated as a strategy to overcome chemoresistance in NSCLC. Tumors from NSCLC patients showed an increase in their profile of pluripotent stemness genes. Cisplatin exposure induced the emergence or expansion of an ALDH1-positive subpopulation in cisplatin sensitive and resistant NSCLC cell lines, respectively, further enhancing cisplatin resistance. Using the Aldefluor assay and FACS analysis, ALDH1 subpopulations were isolated and evaluated in terms of stem cell characteristics. Only ALDH1-positive cells exhibited asymmetric division, cisplatin resistance and increased expression of stem cell factors in vitro. Xenograft studies in NOD/SCID mice demonstrated efficient tumorigenesis from low cell numbers of ALDH1-positive and ALDH1-negative subpopulations. Targeting ALDH1 with Diethylaminobenzaldehyde (DEAB) and Disulfiram, significantly re-sensitized resistant lung cancer cells to the cytotoxic effects of cisplatin. Our data demonstrate the existence of a lung CSC population and suggest a role for targeting ALDH1 as a potential therapeutic strategy in re-sensitizing NSCLC cells to the cytotoxic effects of cisplatin.

Research Papers

Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes

DOI: 10.18632/oncotarget.15647

Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Hironori Ninomiya, Rie Sakakibara, Sophia Subat, Hiroko Nagano, Kimie Nomura, Sakae Okumura, Tomoko Shibutani and Yuichi Ishikawa _

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

TROP2 is a transmembrane glycoprotein that is overexpressed in various cancers. Emerging evidence suggests that TROP2-targeting therapies are efficacious and safe in patients with multiple prior treatments. TROP2 is a promising target for lung cancer treatment; however, little is known regarding the association of TROP2 expression with clinicopathological/molecular features, including prognosis, in lung cancer. We examined consecutive cases of adenocarcinoma, squamous cell carcinoma (SqCC), and high-grade neuroendocrine tumor (HGNET) for the membranous expression of TROP2 using immunohistochemistry. High TROP2 expression was observed in 64% (172/270) of adenocarcinomas, 75% (150/201) of SqCCs, and 18% (21/115) of HGNETs. Intriguingly, the association of TROP2 expression with mortality was dependent on the lung cancer subtype. High TROP2 expression was associated with higher lung cancer-specific mortality in adenocarcinomas [univariable hazard ratio (HR) = 1.60, 95% confidence interval (CI) = 1.07–2.44, P = 0.022)], but not in SqCCs (univariable HR = 0.79, 95% CI = 0.35–1.94, P = 0.79). In HGNETs, high TROP2 expression was associated with lower lung cancer-specific mortality in both univariable and multivariable analyses (multivariable HR = 0.13, 95% CI = 0.020–0.44, P = 0.0003). Our results suggest a differential role for TROP2 in different lung cancer subtypes.

Research Papers

Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model

DOI: 10.18632/oncotarget.2592

Zhuo Zhang _, Hiroe Shiratsuchi, Jules Lin, Guoan Chen, Rishindra M. Reddy, Ebrahim Azizi, Shamileh Fouladdel, Andrew C. Chang, Lin Lin, Hui Jiang, Meghna Waghray, Gary Luker, Diane M. Simeone, Max S. Wicha, David G. Beer, Nithya Ramnath and Sunitha Nagrath

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

The potential utility of circulating tumor cells (CTCs) to guide clinical care in oncology patients has gained momentum with emerging micro- and nanotechnologies. Establishing the role of CTCs in tumor progression and metastasis depends both on enumeration and on obtaining sufficient numbers of CTCs for downstream assays. The numbers of CTCs are few in early stages of cancer, limiting detailed molecular characterization. Recent attempts in the literature to culture CTCs isolated from metastatic patients using monoculture have had limited success rates of less than 20%. Herein, we have developed a novel in-situ capture and culture methodology for ex-vivo expansion of CTCs using a three dimensional co-culture model, simulating a tumor microenvironment to support tumor development. We have successfully expanded CTCs isolated from 14 of 19 early stage lung cancer patients. Expanded lung CTCs carried mutations of the TP53 gene identical to those observed in the matched primary tumors. Next-generation sequencing further revealed additional matched mutations between primary tumor and CTCs of cancer-related genes. This strategy sets the stage to further characterize the biology of CTCs derived from patients with early lung cancers, thereby leading to a better understanding of these putative drivers of metastasis.

Meta-Analysis

Relationship between exposure to PM2.5 and lung cancer incidence and mortality: A meta-analysis

DOI: 10.18632/oncotarget.17313

Feifei Huang, Bing Pan, Jun Wu, Engeng Chen and Liying Chen _

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

We conducted a meta-analysis to examinine the relationship between exposure to PM2.5 and lung cancer incidence and mortality. In total, 17 studies met our inclusion criteria and provided information necessary to estimate the change in lung cancer risk per 10 μg/m3 increase in exposure to PM2.5. The random-effects model was used to estimate the relative risk (RR) for specific PM2.5 values. The meta-estimate for lung cancer risk associated with PM2.5 was 1.11 for mortality (95% CI: 1.05, 1.18) and 1.08 (95% CI: 1.03, 1.12) for incidence. Analyses by continent showed that the meta-estimate for lung cancer mortality associated with PM2.5 was greatest in North America [1.15 (95% CI: 1.07, 1.24)], followed by Asia [1.12 (95% CI: 0.94, 1.35)], and then Europe [1.05 (95% CI: 1.01, 1.10)]. Lung cancer incidence associated with PM2.5 was greatest in Asia [1.09 (95% CI: 1.03, 1.15)], followed by North America [1.06 (95% CI: 1.01, 1.11)], and then Europe [1.03 (95% CI: 0.61, 1.75)]. In subgroup analyses of country, the mortality meta-estimate for developed countries was 1.14 (95% CI: 1.06, 1.23), and for developing countries was 1.03 (95% CI: 1.00, 1.07). The incidence meta-estimate for developed countries was 1.07 (95% CI: 0.96, 1.20), and was similar to that of developing countries, 1.07 (95% CI: 1.06, 1.09). In subgroup analyses of males and females, the meta-estimate for lung cancer mortality associated with PM2.5 was greater for males [1.26 (95% CI: 1.15, 1.40)] than for females [1.17 (95% CI: 0.98, 1.39)]. The meta-estimate for lung cancer incidence associated with PM2.5 was greater for males [1.23 (95% CI: 0.83, 1.81)] than for females [1.15 (95% CI: 1.12, 1.18)]. In subgroup analyses of smoking status, the meta-estimate for lung cancer mortality associated with PM2.5 for former smokers was 1.46 (95% CI: 0.84, 2.55), for current smokers was 1.33 (95% CI: 1.20, 1.49), and for never smokers was 1.16 (95% CI: 1.02, 1.33), respectively. The meta-estimate for lung cancer incidence associated with PM2.5 for former smokers was 1.19 (95% CI: 0.95, 1.50), for never smokers was 1.10 (95% CI: 0.76, 1.59), and for current smokers was 1.03 (95% CI: 0.87, 1.21). The relative risks of a relationship between PM2.5 and lung cancer incidence and mortality were 1.08 (95% CI: 1.03, 1.12) and 1.11 (95% CI: 1.05, 1.18), respectively. These findings will provide some evidence for policy makers and public health practitioners worldwide.

Research Papers

Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer

DOI: 10.18632/oncotarget.3472

Igor F. Tsigelny, Jennifer J. Wheler, Jerry P. Greenberg, Valentina L. Kouznetsova, David J. Stewart, Lyudmila Bazhenova and Razelle Kurzrock _

Abstract | PDF | HTML | Altmetric Report

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.

In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene.

Research Papers

Mitochondrial markers predict survival and progression in non-small cell lung cancer (NSCLC) patients: Use as companion diagnostics

DOI: 10.18632/oncotarget.19677

Federica Sotgia and Michael P. Lisanti _

Abstract | PDF | HTML | Altmetric Report

Here, we used an informatics-based approach to identify novel biomarkers of overall survival and tumor progression in non-small cell lung cancer (NSCLC) patients. We determined whether nuclear-encoded genes associated with mitochondrial biogenesis and function can be used to effectively predict clinical outcome in lung cancer. This strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large, clinically-relevant, lung cancer patient populations. Towards this end, we used a group of 726 lung cancer patients, with negative surgical margins. Importantly, in this group of cancer patients, markers of cell proliferation (Ki67 and PCNA) were associated with poor overall survival, as would be expected. Similarly, key markers of inflammation (CD163 and CD68) also predicted poor clinical outcome in this patient population. Using this approach, we identified >180 new individual mitochondrial gene probes that effectively predicted significantly reduced overall survival, with hazard-ratios (HR) of up to 4.89 (p<1.0e-16). These nuclear-encoded mitochondrial genes included chaperones, membrane proteins as well as ribosomal proteins (MRPs) and components of the OXPHOS (I-V) complexes. In this analysis, HSPD1, a key marker of mitochondrial biogenesis, had the highest predictive value and was also effective in predicting tumor progression in both smokers and non-smokers alike. In fact, it had even higher predictive value in non-smokers (HR=5.9; p=3.9e-07). Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target, for the more effective treatment of human lung cancers. The mitochondrial biomarkers that we have identified could serve as new companion diagnostics to assist clinicians in more accurately predicting clinical outcomes in lung cancer patients, driving more personalized cancer therapy.

Research Papers

The role of EGFR mutations in predicting recurrence in early and locally advanced lung adenocarcinoma following definitive therapy

DOI: 10.18632/oncotarget.27602

Carlos Galvez _, Saya Jacob, Brian S. Finkelman, Jeffrey Zhao, Kyle Tegtmeyer, Young Kwang Chae, Nisha Mohindra, Ravi Salgia, Borko Jovanovic, Amir Behdad and Victoria Villaflor

Abstract | PDF | HTML | Altmetric Report | Press Release

Introduction: Roughly one third of new non-small cell lung cancer (NSCLC) is diagnosed at early stages. While lobectomy can improve mortality in this group, about 30–55% of patients will experience disease recurrence. Increased investigation into the factors affecting recurrence, particularly tumor molecular genetics such as EGFR mutations, is needed.

Materials and Methods: We conducted a single-center retrospective study of 282 patients with early or locally advanced lung adenocarcinoma, with or without EGFR mutations, who underwent definitive therapy. We then assessed recurrence, stage at recurrence, time to recurrence and progression-free survival (PFS).

Results: We identified 142 patients with EGFR-mutated and 140 EGFR-wildtype lung adenocarcinoma. Overall progression between groups was equivalent at ~40% at 5 years; no difference in PFS was observed at any time-point. However, among those who recurred, EGFR-mutated lung cancer had increased rates of metastatic recurrence compared to EGFR-wildtype disease (97% vs 68%, p = 0.007).

Conclusions: EGFR-mutated disease may be associated with a higher risk of metastatic recurrence. Molecular testing may be a promising tool for risk stratification and surveillance following definitive management for early stage disease. Future prospective, multi-center cohort studies are needed to confirm these findings and improve our understanding of how EGFR mutation contributes to prognosis and clinical outcomes.

Research Papers

Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer

DOI: 10.18632/oncotarget.14427

Alessandro Russo _, Tindara Franchina, Giuseppina Rosaria Rita Ricciardi, Caterina Fanizza, Antonino Scimone, Giuseppe Chiofalo, Antonio Giordano and Vincenzo Adamo

Abstract | PDF | HTML | Altmetric Report

Epidermal Growth Factor Receptor (EGFR) mutated Non Small Cell Lung Cancers (NSCLCs) are a molecularly subgroup of patients with peculiar clinic-pathological characteristics. Previous studies have suggested a possible interaction between oncogene status and metastatic behavior in non squamous NSCLCs with conflicting results. The aim of this study was to compare the different metastatic patterns, at baseline and during the course of the disease, in a cohort of 137 Caucasian patients with non-squamous NSCLC according to the EGFR mutational status and survival differences according to the different metastatic behavior. We observed unique metastatic distributions between EGFR-mutated and EGFR wild type non-squamous NSCLCs. These data support the hypothesis that tumor bio-molecular characteristics and genotype may influence the metastatic process in NSCLC and might help the development of enrichment strategies for tumor genotyping in these tumors, especially in the presence of limited tissue availability.

Research Papers

Correction of the NSE concentration in hemolyzed serum samples improves its diagnostic accuracy in small-cell lung cancer

DOI: 10.18632/oncotarget.27664

Sylvia A.A.M. Genet, Esther Visser, Ben E.E.M. van den Borne, Maggy Youssef-El Soud, Huub N.A. Belderbos, Gerben Stege, Marleen E.A. de Saegher, Federica Eduati, Maarten A.C. Broeren, Joost van Dongen, Luc Brunsveld, Daan van de Kerkhof _ and Volkher Scharnhorst

Abstract | PDF | HTML | Supplementary Files | Altmetric Report | Press Release

Neuron-specific enolase (NSE) is a well-known biomarker for the diagnosis, prognosis and treatment monitoring of small-cell lung cancer (SCLC). Nevertheless, its clinical applicability is limited since serum NSE levels are influenced by hemolysis, leading to falsely elevated results. Therefore, this study aimed to develop a hemolysis correction equation and evaluate its role in SCLC diagnostics.

Two serum pools were spiked with increasing amounts of hemolysate obtained from multiple individuals. A hemolysis correction equation was obtained by analyzing the relationship between the measured NSE concentration and the degree of hemolysis. The equation was validated using intentionally hemolyzed serum samples, which showed that the correction was accurate for samples with an H-index up to 30 μmol/L. Correction of the measured NSE concentration in patients suspected of lung cancer caused an increase in AUC and a significantly lower cut-off value for SCLC detection when compared to uncorrected results.

Therefore, a hemolysis correction equation should be used to correct falsely elevated NSE concentrations. Results of samples with an H-index above 30 μmol/L should not be reported to clinicians. Application of the equation illustrates the importance of hemolysis correction in SCLC diagnostics and questions the correctness of the currently used diagnostic cut-off value.

Research Papers

Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study

DOI: 10.18632/oncotarget.27472

Beatrice Aramini _, Federico Banchelli, Stefania Bettelli, Samantha Manfredini, Roberto D’Amico, Valentina Masciale, Massimo Pinelli, Margherita Moretti, Alessandro Stefani, Federica Bertolini, Massimo Dominici, Uliano Morandi and Antonino Maiorana

Abstract | PDF | HTML | Supplementary Files | Altmetric Report | Press Release

Objective: In addition to the most common somatic lung cancer mutations (i. e., KRAS and EGFR mutations), other genes may harbor mutations that could be relevant for lung cancer. We defined BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations as “niche” mutations and analyzed. The aim of this retrospective cohort study was to assess the differences in the overall survival (OS) of patients with lung adenocarcinoma harboring niche somatic mutations.

Results: Data were gathered for 252 patients. Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET. The multivariable analysis showed that 1) niche mutations had a higher mortality than EGFR mutations (HR = 2.3; 95% CI = 1.2–4.4; p = 0.009); 2) KRAS mutations had a higher mortality than EGFR mutations (HR = 2.5; 95% CI = 1.4–4.5; p = 0.003); 3) niche mutations presented a similar mortality to KRAS mutations (HR = 0.9; 95% CI = 0.6–1.5; p = 0.797).

Methods: Three cohorts of mutations were selected from patients with lung adenocarcinoma and their OS was compared. Mutations that were searched for, were 1) BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET; 2) K-RAS; and 3) EGFR. Differences in OS between these three cohorts were assessed by means of a multivariable Cox model that adjusted for age, sex, smoking habits, clinical stages, and treatments.

Conclusions: Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations.

Research Papers

CHL1 gene polymorphisms increase lung cancer susceptibility

DOI: 10.18632/oncotarget.24057

Wen Tian _, Xuelian Li, Yangwu Ren, Zhihua Yin, Xiaowei Quan, Chang Zheng and Baosen Zhou

Abstract | PDF | HTML | Altmetric Report

Lung cancer represents a complex and malignant cancer. Close Homologue of L1 (CHL1) gene plays a crucial role in the progress of cancer. The aim of this study is to explore the association between CHL1 rs425366 polymorphism and lung cancer susceptibility in northeast of China. A hospital-based case-control study was carried out to collect relative characteristics. Logistic regression analysis was conducted to analyze the relationship between single nucleotide polymorphisms and lung cancer susceptibility. The results suggested that there was statistically significant difference between GT genotype and TT genotype of rs425366 and lung cancer susceptibility. In stratified analysis, TT genotype of rs425366 may increase the risk of lung adenocarcinoma. We also found that non-smoking individuals carrying T allele were more likely to develop lung cancer. Overall, our study may indicate that CHL1 gene may increase lung cancer susceptibility in northeast of China.

Research Papers

Integrative system genetic analysis reveals mRNA-lncRNA network associated with mouse spontaneous lung cancer susceptibility

DOI: 10.18632/oncotarget.26554

Yu Zhou _ and Ming You

Abstract | PDF | HTML | Altmetric Report

Introduction: Lung cancer continues to be a significant health burden in the United States. Lung cancer in never smokers is considered as a different disease and underlying mechanism of spontaneous lung cancer susceptibility is still poorly known. Meanwhile, the roles of long non-coding RNAs (lncRNAs), which have multiple functions in biological processes, have seldom been studied in spontaneous lung cancer susceptibility.

Methods: In this study, microarray analyses of normal lung tissues were performed in 23 different mouse strains. LncRNA profile was analyzed by re-annotating exon array for lncRNAs detection. LncRNA/mRNA co-expression networks were constructed and the association between significant lncRNA module and significant mRNA modules was calculated. Finally, Genome-wide association (GWA) results were used to further highlight the key mRNAs and lncRNAs associated with spontaneous lung cancer susceptibility.

Results: Four mRNA modules were significantly associated with spontaneous lung cancer susceptibility. Genes in these modules were enriched in “blood coagulation” and “immune system process”. Only one lncRNA module was significantly associated with spontaneous lung cancer susceptibility. Many lncRNAs in this module were co-expressed with mRNAs in the second most significant mRNA module. This co-expression network contained 113 interactions between 30 lncRNAs and 40 mRNAs. After GWA filtration, two mRNAs (Myo7a and Zfp874a) and two lncRNAs (n290048 and n271850) were highlighted as the candidates responsible for genetic susceptibility to lung cancer.

Conclusions: We firstly used integrative system genetic analysis to report the mRNA-lncRNA network associated with spontaneous lung cancer susceptibility and identified potential targets for lung cancer prevention.

Research Papers

Immune checkpoint inhibitor re-challenge in patients with advanced non-small cell lung cancer

DOI: 10.18632/oncotarget.25949

Maiko Niki, Aya Nakaya _, Takayasu Kurata, Hiroshige Yoshioka, Toshihiko Kaneda, Kayoko Kibata, Makoto Ogata and Shosaku Nomura

Abstract | PDF | HTML | Altmetric Report

Background: Immune checkpoint inhibitors have dramatically changed lung cancer treatment, demonstrating an overall survival benefit. There are limited data about re-challenge in patients with non-small cell lung cancer. We attempted to address this question for re-challenge of immune checkpoint inhibitor in patients with advanced non-small cell lung cancer.

Methods: We retrospectively analyzed 11 patients with advanced non-small cell lung cancer treated with nivolumab and re-challenged with nivolumab/pemblorizumab at Kansai Medical University Hospital from December 2015 to December 2017.

Results: Three patients achieved PR and two patients were in SD. These patients were apt to be good responders to the initial treatment, to develop immune-related adverse events and to be immediately started on re-challenge with immune checkpoint inhibitor. The median PFS was 2.7 (range, 0.5–16.1) months. Five patients (45%) had mild to moderate immune-related adverse events.

Conclusion: Our study shows the effectiveness of re-challenge of immune checkpoint inhibitors in a subset of non-small cell lung cancer patients. Re-challenge might become one of treatment option for advanced non-small cell lung cancer.

Research Papers

The microtubule-associated protein PRC1 is a potential therapeutic target for lung cancer

DOI: 10.18632/oncotarget.23577

Steffen Hanselmann, Patrick Wolter, Jonas Malkmus and Stefan Gaubatz _

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

In this study, we investigated whether proteins that are involved in cytokinesis are potential targets for therapy of lung cancer. We find that the microtubule-associated protein PRC1 (protein required for cytokinesis 1), which plays a key role in organizing anti-parallel microtubule in the central spindle in cytokinesis, is overexpressed in lung cancer cell lines compared to normal cells. Increased expression of PRC1 is correlated with a poor prognosis of human lung adenocarcinoma patients. Lentiviral delivered, inducible RNAi of PRC1 demonstrated that proliferation of lung cancer cell lines strongly depends on PRC1. Significantly, we also show that PRC1 is required for tumorigenesis in vivo using a mouse model for non-small cell lung cancer driven by oncogenic K-RAS and loss of p53. When PRC1 is depleted by in vivo RNA interference, lung tumor formation is significantly reduced. Although PRC1 has been suggested to regulate Wnt/ß-catenin signaling in cancer cells, we find no evidence for a role of PRC1 in this pathway in lung cancer. Instead, we show that the depletion of PRC1 results in a strong increase in bi- and multinuclear cells due to defects in cytokinesis. This ultimately leads to apoptosis and senescence. Together these data establish PRC1 as a potential target for therapy of lung cancer.

Research Papers

EYA2 promotes lung cancer cell proliferation by downregulating the expression of PTEN

DOI: 10.18632/oncotarget.22860

Zhaoming Li, Ran Qiu, Xia Qiu and Tian Tian _

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

Lung cancer is the leading cause of cancer-related death worldwide. Despite advances have been made in diagnosis and therapeutic strategies, the prognosis of lung cancer is still very poor. Eyes absent transcriptional cofactor EYA2 has been shown to promote lung cancer cell growth, however, the underlying molecular mechanism is still not fully understood. In the present study, we found that EYA2 was up-regulated in lung cancer, and EYA2 led to increased cell proliferation by inhibiting Phosphatase and tensin homologue (PTEN) expression via modulation of miR-93. Additionally, survival analysis showed that lung cancer patients with higher EYA2 expression predicted a worse prognosis. Therefore, these findings demonstrate that EYA2 may play an important role in lung cancer occurrence and progression. Targeting EYA2 may provide a feasible approach in developing novel anticancer therapeutics.

Research Papers

MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion

DOI: 10.18632/oncotarget.24203

Madiha Kanwal _, Xiao-Jie Ding, Xin Song, Guang-Biao Zhou and Yi Cao

Abstract | PDF | HTML | Supplementary Files | Altmetric Report

Air pollution is one of the leading causes of lung cancer. Air pollution-related lung cancer is a deteriorating public health problem, particularly in developing countries. The MUC16 gene is one of the most frequently mutated genes in air pollution-related lung cancer. In the present study, MUC16 mRNA expression was increased in ~50% of air pollution-related lung cancer samples obtained from patients residing in air-polluted regions (Xuanwei and Fuyuan, Yunnan, China), and MUC16 mRNA levels were correlated with the degree of air pollution. Furthermore, sequencing of the captured MUC16 gene identified 561 mutation sites within the MUC16 gene in the air pollution-related lung cancer tissues. Interestingly, some mutations at specific sites and one region were associated with MUC16 mRNA up-regulation. Therefore, we further investigated the impacts of gene mutation on MUC16 expressions and cell behaviors in cultured cells by inducing certain mutations within the MUC16 gene using CRISPER/Cas9 genome editing technology. Certain mutations within the MUC16 gene induced MUC16 overexpression at both the mRNA and the protein level in the cultured cells. Additionally, MUC16 overexpression induced by gene mutations had functional effects on the behavior of lung cancer cells, including increasing their resistance to cisplatin, promoting their growth, and enhancing their migration and invasion capabilities. Based on the data, we suggest that MUC16 mutations potentially associated with air pollution may participate in the development and progression of air pollution-related lung cancer. In addition to ovarian cancer, MUC16 may be a candidate biomarker for lung cancer.

Research Papers

Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma

DOI: 10.18632/oncotarget.10653

Michele Carbone _, David Shimizu, Andrea Napolitano, Mika Tanji, Harvey I. Pass, Haining Yang and Sandra Pastorino

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The differential diagnosis between pleural malignant mesothelioma (MM) and lung cancer is often challenging. Immunohistochemical (IHC) stains used to distinguish these malignancies include markers that are most often positive in MM and less frequently positive in carcinomas, and vice versa. However, in about 10–20% of the cases, the IHC results can be confusing and inconclusive, and novel markers are sought to increase the diagnostic accuracy.

We stained 45 non-small cell lung cancer samples (32 adenocarcinomas and 13 squamous cell carcinomas) with a monoclonal antibody for BRCA1-associated protein 1 (BAP1) and also with an IHC panel we routinely use to help differentiate MM from carcinomas, which include, calretinin, Wilms Tumor 1, cytokeratin 5, podoplanin D2-40, pankeratin CAM5.2, thyroid transcription factor 1, Napsin-A, and p63. Nuclear BAP1 expression was also analyzed in 35 MM biopsies. All 45 non-small cell lung cancer biopsies stained positive for nuclear BAP1, whereas 22/35 (63%) MM biopsies lacked nuclear BAP1 staining, consistent with previous data. Lack of BAP1 nuclear staining was associated with MM (two-tailed Fisher’s Exact Test, P = 5.4 x 10-11). Focal BAP1 staining was observed in a subset of samples, suggesting polyclonality. Diagnostic accuracy of other classical IHC markers was in agreement with previous studies. Our study indicated that absence of nuclear BAP1 stain helps differentiate MM from lung carcinomas. We suggest that BAP1 staining should be added to the IHC panel that is currently used to distinguish these malignancies.

Research Papers

RASSF1C regulates miR-33a and EMT marker gene expression in lung cancer cells

DOI: 10.18632/oncotarget.26498

Yousef G. Amaar _ and Mark E. Reeves

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RASSF1C functions as an oncogene in lung cancer cells by stimulating proliferation and migration, and reducing apoptosis. Further, RASSF1C up-regulates important protein-coding and non-coding genes involved in lung cancer cell growth, including the stem cell self-renewal gene, piwil1, and small noncoding PIWI-interacting RNAs (piRNAs). In this article, we report the identification of microRNAs (miRNAs) that are modulated in lung cancer cells over-expressing RASSF1C. A lung cancer-specific miRNA PCR array screen was performed to identify RASSF1C target miRNA-coding genes using RNA isolated from the lung cancer cell line H1299 stably over-expressing RASSF1C and corresponding control. Several modulated miRNA genes were identified that are important in cancer cell proliferation and survival. Among the miRNAs down-regulated by RASSF1C is miRNA-33a-5p (miRNA-33a), which functions as a tumor suppressor in lung cancer cells. We validated that over-expression of RASSF1C down-regulates miR-33a expression and RASSF1C knockdown up-regulates miR-33a expression. We found that RASSF1C over-expression also increases β-catenin, vimentin, and snail protein levels in cells over-expressing miR-33a. In addition, we found that RASSF1C up-regulates the expression of ABCA1 mRNA which is a known target of miR-33a. Our findings suggest that RASSF1C may promote lung epithelial mesenchymal transition (EMT), resulting in the development of a lung cancer stem cell phenotype, progression, and metastasis, in part, through modulation of miR-33a expression. Our findings reveal a new mechanistic insight into how RASSF1C functions as an oncogene.

Reviews

Lung cancer and chronic obstructive pulmonary disease: From a clinical perspective

DOI: 10.18632/oncotarget.14505

Jie Dai, Ping Yang, Angela Cox and Gening Jiang _

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Chronic obstructive pulmonary disease (COPD) and lung cancer are devastating pulmonary diseases that commonly coexist and present a number of clinical challenges. COPD confers a higher risk for lung cancer development, but available chemopreventive measures remain rudimentary. Current studies have shown a marked benefit of cancer screening in the COPD population, although challenges remain, including the common underdiagnosis of COPD. COPD-associated lung cancer presents distinct clinical features. Treatment for lung cancer coexisting with COPD is challenging as COPD may increase postoperative morbidities and decrease survival. In this review, we outline current progress in the understanding of the clinical association between COPD and lung cancer, and suggest possible cancer prevention strategies in this patient population.

Research Papers

miR-30a suppresses lung cancer progression by targeting SIRT1

DOI: 10.18632/oncotarget.23529

Yaowu Guan _, Zhongming Rao and Cheng Chen

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The class III histone deacetylase silent information regulator 1 (SIRT1) is frequently overexpressed in a variety of tumors, including lung cancer; however, its regulatory mechanisms are largely unknown. In this study, we found that an inconsistent trend between SIRT1 protein and mRNA levels in human lung cancer tissues, suggesting that a post-transcriptional mechanism may involved in SIRT1 regulation. Because microRNAs are important post-transcriptional regulators of gene expression, candidate miRNAs that could potentially bind SIRT1 were gained through bioinformatics analyses. We further experimentally validated SIRT1 as the direct target of miR-30a by evaluating SIRT1 expression in lung cancer cells after the overexpression or knockdown of miR-30a and by luciferase assay. Moreover, we showed that miR-30a inhibited proliferation, invasion and promoted apoptosis of lung cancer cells by inhibiting SIRT1 in vitro and in vivo. Taken together, this study identified a new regulatory axis in which miR-30a and SIRT1 regulate the proliferation, invasion and apoptosis of lung cancer cells and lung tumorigenesis.

Reviews

Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies

DOI: 10.18632/oncotarget.17016

Qing-Ge Zhu, Shi-Ming Zhang, Xiao-Xiao Ding, Bing He and Hu-Qin Zhang _

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Lung cancer is one of the most common causes of cancer-related death in the world. The large number of lung cancer cases is non-small cell lung cancer (NSCLC), which approximately accounting for 75% of lung cancer. Over the past years, our comprehensive knowledge about the molecular biology of NSCLC has been rapidly enriching, which has promoted the discovery of driver genes in NSCLC and directed FDA-approved targeted therapies. Of course, the targeted therapies based on driver genes provide a more exact option for advanced non-small cell lung cancer, improving the survival rate of patients. Now, we will review the landscape of driver genes in NSCLC including the characteristics, detection methods, the application of target therapy and challenges.

Research Papers

Grape seed procyanidin extract against lung cancer: the role of microrna-106b, bioavailability, and bioactivity

DOI: 10.18632/oncotarget.24528

Bingye Xue, Qing-Yi Lu, Larry Massie, Clifford Qualls and Jenny T. Mao _

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MiR-106b is an oncomir and a potential target for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects on lung cancer through modulations of miR-106b and its downstream target. We found that GSE significantly down-regulated miR-106b in a variety of lung neoplastic cells and increased cyclin-dependent kinase inhibitor 1A (CDKN1A) mRNA and protein (p21) levels. Transfection of miR-106b mimics reversed the up-regulations of CDKN1A mRNA and p21, abrogated the GSE induced anti-proliferative and anti-invasive properties in lung cancer cells. Oral gavage of leucoselect phytosome (LP), a standardized GSE to athymic nude mice down-regulated MIR106B mRNA and miR-106b expressions, and increased CDKN1A mRNA expression in tumor xenografts, correlating to significant reduction of tumor growth. To assess bioavailability, GSE and metabolites in plasma levels, between 60–90 minutes after gavage of LP were measured by LC/MS at treatment week 4 and 8. A novel bioactivity assay was also developed using lung homogenates from treated mice co-cultured with human lung cancer cells. LP-treated mouse lung homogenates significantly reduced proliferations of various lung cancer cells. Our findings reveal novel antineoplastic mechanisms by GSE, further define the pharmacokinetics and pharmacodynamics of LP, and support the continued investigation of LP against lung cancer.

Reviews

Molecular pathways and therapeutic targets in lung cancer

DOI: 10.18632/oncotarget.1891

Emma Shtivelman _, Thomas Hensing, George R. Simon, Phillip A. Dennis, Gregory A. Otterson, Raphael Bueno and Ravi Salgia

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Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.



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