Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.
Stephenson, Natalie L
Marusiak, Anna A
Trotter, Eleanor W
Hudson, Andrew M
Hodgkinson, Cassandra L
Morrow, Christopher J
AffiliationSignalling Networks in Cancer Group, Cancer Research UK Manchester Institute
MetadataShow full item record
AbstractThe 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.
CitationSomatically mutated ABL1 is an actionable and essential NSCLC survival gene. 2016: EMBO Mol Med
JournalEMBO Molecular Medicine
- Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate.
- Authors: Rausch JL, Boichuk S, Ali AA, Patil SS, Liu L, Lee DM, Brown MF, Makielski KR, Liu Y, Taguchi T, Kuan SF, Duensing A
- Issue date: 2017 Jan 17
- Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases.
- Authors: Dasgupta Y, Koptyra M, Hoser G, Kantekure K, Roy D, Gornicka B, Nieborowska-Skorska M, Bolton-Gillespie E, Cerny-Reiterer S, Müschen M, Valent P, Wasik MA, Richardson C, Hantschel O, van der Kuip H, Stoklosa T, Skorski T
- Issue date: 2016 Apr 28
- Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1.
- Authors: Lin J, Sun T, Ji L, Deng W, Roth J, Minna J, Arlinghaus R
- Issue date: 2007 Oct 25
- Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERK pathway.
- Authors: Sun Y, Chen C, Zhang P, Xie H, Hou L, Hui Z, Xu Y, Du Q, Zhou X, Su B, Gao W
- Issue date: 2014 Oct 6
- Incidence and clinical importance of BCR-ABL1 mutations in Iranian patients with chronic myeloid leukemia on imatinib.
- Authors: Rostami G, Hamid M, Yaran M, Khani M, Karimipoor M
- Issue date: 2015 May