title: Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer.
abstract: The targeting of oncogenic 'driver' kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Kurtis D
authors.initials: KD
authors.lastname: Davies
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Mahale
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: David P
authors.initials: DP
authors.lastname: Astling
authors.affiliation: Department of Pathology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Anh T
authors.initials: AT
authors.lastname: Le
authors.affiliation: Department of Craniofacial Biology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Trista K
authors.initials: TK
authors.lastname: Hinz
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Aria
authors.initials: A
authors.lastname: Vaishnavi
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.affiliation: Department of Craniofacial Biology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005784:Gene Amplification / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human