Priority Research Papers:
Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition
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Catherine Wilson1, Katrina Nicholes2, Daisy Bustos2, Eva Lin1, Qinghua Song3, Jean-Philippe Stephan2, Donald S. Kirkpatrick2 and Jeff Settleman1
1 Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA
2 Department of Discovery Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA
3 Department of Discovery Nonclinical Biostatistics, Genentech, 1 DNA Way, South San Francisco, CA
Jeff Settleman, email:
Keywords: EMT, Src, drug resistance, dasatinib, cancer
Received: July 19, 2014 Accepted: August 26, 2014 Published: August 27, 2014
Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, “EGFR-addicted” cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT.
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