title: AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs.
abstract: Molecularly targeted drug therapies have revolutionized cancer treatment; however, resistance remains a major limitation to their overall efficacy. Epithelial-to-mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKI), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase associated with EMT that has been implicated in drug resistance and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple-negative breast cancer and non-small cell lung cancer. In an unbiased screen of small-molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with antimitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. However, we did not find that AXL inhibition alone could overcome acquired resistance to EGFR TKIs in the EMT setting, as previously reported. These findings reveal a novel cotreatment strategy for tumors displaying mesenchymal features that otherwise render them treatment refractory.
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Thinh
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Eva
authors.initials: E
authors.lastname: Lin
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Sara
authors.initials: S
authors.lastname: Chan
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Erin
authors.initials: E
authors.lastname: McNamara
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Neve
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Lisa
authors.initials: L
authors.lastname: Belmont
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, California.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, California. settleman.jeffrey@gene.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D002945:Cisplatin / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition; D000069347:Erlotinib Hydrochloride; D006367:HeLa Cells; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D043823:Taxoids; D016212:Transforming Growth Factor beta; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D020794:Receptor Protein-Tyrosine Kinases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin; D000094963:Axl Receptor Tyrosine Kinase