Reference Detail

Ref Type Journal Article
PMID (26758680)
Authors Testoni E, Stephenson NL, Torres-Ayuso P, Marusiak AA, Trotter EW, Hudson A, Hodgkinson CL, Morrow CJ, Dive C, Brognard J
Title Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.
Journal EMBO molecular medicine
Vol 8
Issue 2
Date 2016 Feb 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
G321L missense gain of function - predicted ABL1 G321L (corresponding to G340L in isoform IB) lies within the protein kinase domain of the Abl1 protein (UniProt.org). G321L does not result in increased phosphorylation of CRKL by Abl1, but leads to increased cytoplasmic Abl1 retention and is associated with increased cell survival in culture, and is predicted to lead to a gain of Abl1 function (PMID: 26758680).
I242M missense unknown ABL1 I242M lies within the protein kinase domain of the Abl1 protein (UniProt.org). I242M has not been fully biochemically characterized, but does not result in expression of the Abl1 protein or phosphorylation of the downstream signaling molecule, Crkl, in vitro (PMID: 26758680) and therefore, its effect on Abl1 protein function is unknown (PubMed, Nov 2018).
R332W missense gain of function ABL1 R332W (corresponding to R351W in isoform IB) lies within the protein kinase domain of the Abl1 protein (UniProt.org). R332W results in increased Abl1 kinase activity, as demonstrated by modest increase in CRKL phosphorylation, and increased cytoplasmic retention of Abl1 in cell culture (PMID: 26758680).
S79F missense unknown CSF3R S79F lies within the Ig-like C2-type domain of the Csf3r protein (UniProt.org). S79F has been identified in sequencing studies (PMID: 26758680), but has not been biochemically characterized and therefore, its effect on Csf3r protein function is unknown (PubMed, Jan 2019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ABL1 R332W lung adenocarcinoma sensitive Dasatinib Preclinical Actionable In a preclinical study, treatment with Sprycel (dasatinib) in decreased CRKL phosphorylation and reduced viability of lung adenocarcinoma cells harboring ABL1 R332W (also reported as R351W) in culture (PMID: 26758680). 26758680
ABL1 G321L lung adenocarcinoma sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited growth of a lung adenocarcinoma cell line harboring ABL1 G321L (also reported as G340L) in culture (PMID: 26758680). 26758680
ABL1 R332W lung adenocarcinoma sensitive Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gleevec (imatinib) inhibited growth of a lung adenocarcinoma cell line harboring ABL1 R332W (also reported as R351W) in culture, and inhibited tumor growth in xenograft models (PMID: 26758680). 26758680
ABL1 G321L lung adenocarcinoma sensitive Dasatinib Preclinical Actionable In a preclinical study, treatment with Sprycel (dasatinib) in decreased CRKL phosphorylation and reduced viability of lung adenocarcinoma cells harboring ABL1 G321L (also reported as G340L) in culture (PMID: 26758680). 26758680
ABL1 R332W ABL1 T315I lung adenocarcinoma resistant Dasatinib Preclinical Actionable In a preclinical study, lung adenocarcinoma cells harboring ABL1 R332W (also reported as R351W) and expressing ABL1 T315I demonstrated resistance to Sprycel (dasatinib) in culture (PMID: 26758680). 26758680
ABL1 R332W ABL1 T315I lung adenocarcinoma resistant Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, lung adenocarcinoma cells harboring ABL1 R332W (also reported as R351W) and expressing ABL1 T315I demonstrated resistance to Gleevec (imatinib) in culture and in xenograft models (PMID: 26758680). 26758680