Reference Detail

Ref Type

Journal Article

PMID

(22649091)

Authors

Sen B, Peng S, Tang X, Erickson HS, Galindo H, Mazumdar T, Stewart DJ, Wistuba I, Johnson FM

Title

Kinase-impaired BRAF mutations in lung cancer confer sensitivity to dasatinib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	4	136	2012 May 30	136ra70	Sci Transl Med

URL

Abstract Text

During a clinical trial of the tyrosine kinase inhibitor dasatinib for advanced non-small cell lung cancer (NSCLC), one patient responded dramatically and remains cancer-free 4 years later. A comprehensive analysis of his tumor revealed a previously undescribed, kinase-inactivating BRAF mutation ((Y472C)BRAF); no inactivating BRAF mutations were found in the nonresponding tumors taken from other patients. Cells transfected with (Y472C)BRAF exhibited CRAF, MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), and ERK (extracellular signal-regulated kinase) activation-characteristics identical to signaling changes that occur with previously known kinase-inactivating BRAF mutants. Dasatinib selectively induced senescence in NSCLC cells with inactivating BRAF mutations. Transfection of other NSCLC cells with these BRAF mutations also increased these cells' dasatinib sensitivity, whereas transfection with an activating BRAF mutation led to their increased dasatinib resistance. The sensitivity induced by (Y472C)BRAF was reversed by the introduction of a BRAF mutation that impairs RAF dimerization. Dasatinib inhibited CRAF modestly, but concurrently induced RAF dimerization, resulting in ERK activation in NSCLC cells with kinase-inactivating BRAF mutations. The sensitivity of NSCLC with kinase-impaired BRAF to dasatinib suggested synthetic lethality of BRAF and an unknown dasatinib target. Inhibiting BRAF in NSCLC cells expressing wild-type BRAF likewise enhanced these cells' dasatinib sensitivity. Thus, the patient's BRAF mutation was likely responsible for his tumor's marked response to dasatinib, suggesting that tumors bearing kinase-impaired BRAF mutations may be exquisitely sensitive to dasatinib. Moreover, the potential synthetic lethality of combination therapy including dasatinib and BRAF inhibitors may lead to additional therapeutic options against cancers with wild-type BRAF.

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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	Associated with drug Resistance
BRAF	G466V	missense	loss of function	BRAF G466V lies within the protein kinase domain of the Braf protein (UniProt.org). G466V results in impaired Braf kinase activity, but paradoxically activates MEK and ERK through transactivation of CRAF in cell culture (PMID: 22649091, PMID: 28783719), and in one of two cell lines, G466V decreased cell proliferation and cell viability as compared to wild-type Braf (PMID: 29533785).
BRAF	Y472C	missense	unknown	BRAF Y472C lies within the protein kinase domain of the Braf protein (UniProt.org). Y472C results in impaired Braf kinase activity, but paradoxically increases Mek and Erk signaling through C-raf transactivation (PMID: 22649091), however in two different cell lines, Y472C induces similar cell proliferation and cell viability as compared to wild-type Braf (PMID: 29533785), and therefore, its effect on Braf protein function is unknown.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	lung carcinoma	resistant	Dasatinib	Preclinical	Actionable	In a preclinical study, Sprycel (dasatinib) failed to induce apoptosis in lung carcinoma cells expressing BRAF V600E (PMID: 22649091).	22649091
BRAF G466V	lung non-small cell carcinoma	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) induced apoptosis in non-small cell lung cancer cells expressing BRAF G466V in culture (PMID: 22649091).	22649091
BRAF Y472C	lung non-small cell carcinoma	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) induced apoptosis in non-small cell lung carcinoma cells harboring BRAF Y472C in culture (PMID: 22649091).	22649091