Oncotarget

Research Papers:

Integrative proteomic and transcriptomic analysis provides evidence for TrkB (NTRK2) as a therapeutic target in combination with tyrosine kinase inhibitors for non-small cell lung cancer

Daniel Richard Gomez _, Lauren Averett Byers, Monique Nilsson, Lixia Diao, Jing Wang, Lerong Li, Pan Tong, Mia Hofstad, Babita Saigal, Ignacio Wistuba, Neda Kalhor, Stephen Swisher, Youhong Fan, Waun Ki Hong, Milind Suraokar, Carmen Behrens, Cesar Moran and John Victor Heymach

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Oncotarget. 2018; 9:14268-14284. https://doi.org/10.18632/oncotarget.24361

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Abstract

Daniel Richard Gomez1,*, Lauren Averett Byers2,*, Monique Nilsson2, Lixia Diao3, Jing Wang3, Lerong Li3, Pan Tong3, Mia Hofstad2, Babita Saigal2, Ignacio Wistuba4, Neda Kalhor5, Stephen Swisher6, Youhong Fan5, Waun Ki Hong2, Milind Suraokar2, Carmen Behrens2, Cesar Moran5 and John Victor Heymach2

1Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Department of Thoracic/Head and Neck Medical Oncology, University of Texas Anderson Cancer Center, Houston, TX, USA

3Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA

4Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

5Department of Pathology Administration, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

6Department of Thoracic and Cardiovascular Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

*These authors have contributed equally to this work

Correspondence to:

Daniel Richard Gomez, email: dgomez@mdanderson.org

Keywords: TrkB; squamous cell carcinoma; lung cancer; proteomics

Received: October 20, 2016     Accepted: November 10, 2017     Epub: January 30, 2018    Published: March 06, 2018

ABSTRACT

While several molecular targets have been identified for adenocarcinoma (ACA) of the lung, similar drivers with squamous cell carcinoma (SCC) are sparse. We compared signaling pathways and potential therapeutic targets in lung SCC and ACA tumors using reverse phase proteomic arrays (RPPA) from two independent cohorts of resected early stage NSCLC patients: a testing set using an MDACC cohort (N=140) and a validation set using the Cancer Genome Atlas (TCGA) cohorts. We identified multiple potentially targetable proteins upregulated in SCC, including NRF2, Keap1, PARP, TrkB, and Chk2. Of these potential targets, we found that TrkB also had significant increases in gene expression in SCC as compared to adenocarcinoma. Thus, we next validated the upregulation of TrkB both in vitro and in vivo and found that it was constitutively expressed at high levels in a subset of SCC cell lines. Furthermore, we found that TrkB inhibition suppressed tumor growth, invasiveness and sensitized SCC cells to tyrosine kinase EGFR inhibition in a cell-specific manner.


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