Open AccessSomatically mutated ABL 1 is an actionable and essential NSCLC survival gene
Author(s) -
Testoni Ewelina,
Stephenson Natalie L,
TorresAyuso Pedro,
Marusiak Anna A,
Trotter Eleanor W,
Hudson Andrew,
Hodgkinson Cassandra L,
Morrow Christopher J,
Dive Caroline,
Brognard John
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505456
Subject(s) - abl , imatinib , cancer research , biology , mutation , lung cancer , protein kinase domain , dasatinib , mutant , kinase , medicine , tyrosine kinase , gene , signal transduction , genetics , oncology , myeloid leukemia
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 ABL 1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells with ABL 1 mutations are sensitive to ABL inhibitors and we verify that the drug‐induced effects on cell viability are specific to pharmacological inhibition of the ABL 1 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 ABL 1. Consistent with structural modeling, we demonstrate that mutations in ABL 1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild‐type ABL 1. Finally, we observe that the ABL 1 cancer mutants display an increased cytosolic localization, which is associated with the oncogenic properties of the ABL 1 kinase. In summary, our results suggest that NSCLC patients with ABL 1 mutations could be stratified for treatment with imatinib in combination with other therapies.