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	Vol	Issue	Date	Pages	Journal Short Title
EMBO molecular medicine	8	2	2016 Feb 01	105-16	EMBO Mol Med

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
ABL1	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 (PMID: 26758680), and therefore, is predicted to lead to a gain of Abl1 protein function.
ABL1	I242M	missense	unknown	ABL1 I242M lies within the protein kinase domain of the Abl1 protein (UniProt.org). I242M does not result in expression of the Abl1 protein or phosphorylation of the downstream signaling molecule Crkl in culture (PMID: 26758680), but has not been fully biochemically characterized and therefore, its effect on Abl1 protein function is unknown.
ABL1	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).
CSF3R	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, Aug 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 T315I ABL1 R332W	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
ABL1 T315I ABL1 R332W	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	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 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	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