title: Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.
abstract: The lack of actionable mutations in patients with non-small cell lung cancer (NSCLC) presents a significant hurdle in the design of targeted therapies for this disease. Here, we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug-induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Furthermore, we confirm that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we observe that the ABL1 cancer mutants display an increased cytosolic localization, which is associated with the oncogenic properties of the ABL1 kinase. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies.
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Testoni
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Stephenson
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Pedro
authors.initials: P
authors.lastname: Torres-Ayuso
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Marusiak
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Eleanor W
authors.initials: EW
authors.lastname: Trotter
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hudson
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK john.brognard@cruk.manchester.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Brognard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl
keywords: ABL1 mutations; dasatinib; imatinib; non‐small cell lung cancer