Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.
Authors
Testoni, EwelinaStephenson, Natalie L
Torres-Ayuso, Pedro
Marusiak, Anna A
Trotter, Eleanor W
Hudson, Andrew M
Hodgkinson, Cassandra L
Morrow, Christopher J
Dive, Caroline
Brognard, John
Affiliation
Signalling Networks in Cancer Group, Cancer Research UK Manchester InstituteIssue Date
2016-01-12
Metadata
Show full item recordAbstract
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.Citation
Somatically mutated ABL1 is an actionable and essential NSCLC survival gene. 2016: EMBO Mol MedJournal
EMBO Molecular MedicineDOI
10.15252/emmm.201505456PubMed ID
26758680Type
ArticleLanguage
enISSN
1757-4684ae974a485f413a2113503eed53cd6c53
10.15252/emmm.201505456