title: Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition.
abstract: 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.
authors.affiliation: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Discovery Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Nicholes
authors.affiliation: Department of Discovery Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Bustos
authors.affiliation: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Eva
authors.initials: E
authors.lastname: Lin
authors.affiliation: Department of Discovery Nonclinical Biostatistics, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Discovery Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.affiliation: Department of Discovery Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.affiliation: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D018773:Genes, erbB-1; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D000069439:Dasatinib