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
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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
Daniel Richard Gomez, email: [email protected]
Keywords: TrkB; squamous cell carcinoma; lung cancer; proteomics
Received: October 20, 2016 Accepted: November 10, 2017 Epub: January 30, 2018 Published: March 06, 2018
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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