Oncotarget

Research Papers:

Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells

Haiying Cheng _, Zhenfeng Zhang, Ruth Rodriguez-Barrueco, Alain Borczuk, Huijie Liu, Jiyang Yu, Jose M. Silva, Simon K. Cheng, Roman Perez-Soler and Balazs Halmos

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Oncotarget. 2016; 7:28976-28988. https://doi.org/10.18632/oncotarget.6721

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Abstract

Haiying Cheng1, Zhenfeng Zhang2, Ruth Rodriguez-Barrueco3, Alain Borczuk4, Huijie Liu1, Jiyang Yu5,7, Jose M. Silva3, Simon K. Cheng6, Roman Perez-Soler1, Balazs Halmos1,8

1Department of Oncology, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, NY, USA

2Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Center of Medical Imaging and Image-Guided Therapy, Guangzhou, China

3Icahn School of Medicine at Mount Sinai, New York, NY, USA

4Department of Pathology, Weill Cornell University Medical Center, New York, NY, USA

5Department of Biomedical Informatics, Columbia University, New York, NY, USA

6Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, New York, NY, USA

7Department of Precision Medicine, Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA

8Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY, USA

Correspondence to:

Haiying Cheng, email: hcheng@montefiore.org

Keywords: lung cancer, RNAi screen, YAP1, platinum resistance, radiation

Received: August 27, 2015     Accepted: November 21, 2015     Published: December 22, 2015

ABSTRACT

Survival for lung cancer patients remains dismal and is largely attributed to treatment resistance. To identify novel target genes the modulation of which could modify platinum resistance, we performed a high-throughput RNAi screen and identified Yes-associated protein (YAP1), a transcription coactivator and a known oncogene, as a potential actionable candidate. YAP1 ablation significantly improved sensitivities not only to cisplatin but also to ionizing radiation, both of which are DNA-damaging interventions, in non-small cell lung cancer (NSCLC) cells. Overall YAP1 was expressed in 75% of NSCLC specimens, whereas nuclear YAP1 which is the active form was present in 45% of 124 resected NSCLC. Interestingly, EGFR-mutated or KRAS-mutated NSCLC were associated with higher nuclear YAP1 staining in comparison to EGFR/KRAS wild-type. Relevantly, YAP1 downregulation improved sensitivity to erlotinib, an EGFR inhibitor. A pharmacological inhibitor of YAP1 signaling, verteporfin also synergized with cisplatin, radiation and erlotinib in NSCLC cells by potentiating cisplatin and radiation-related double-stranded breaks and decreasing expression of YAP1 and EGFR. Taken together, our study is the first to indicate the potential role of YAP1 as a common modulator of resistance mechanisms and a potential novel, actionable target that can improve responses to platinum, radiation and EGFR-targeted therapy in lung cancer.


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