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Ref Type

Journal Article

PMID

(26996308)

Authors

Foster SA, Whalen DM, Özen A, Wongchenko MJ, Yin J, Yen I, Schaefer G, Mayfield JD, Chmielecki J, Stephens PJ, Albacker LA, Yan Y, Song K, Hatzivassiliou G, Eigenbrot C, Yu C, Shaw AS, Manning G, Skelton NJ, Hymowitz SG, Malek S

Title

Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	29	4	2016 Apr 11	477-493	Cancer Cell

URL

Abstract Text

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.

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Showing 1 to 4 of 4 entries

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	K483M	missense	unknown	BRAF K483M (also reported as K482M) lies within an ATP binding site in the protein kinase domain of the Braf protein (UniProt.org). K483M results in a loss of Braf kinase activity, however, has been demonstrated to both activate MEK through CRAF (PMID: 16508002, PMID: 23533272, PMID: 26996308), and lacks the ability to activate ERK and CRAF in cell culture and in Xenopus (PMID: 15035987, PMID: 30828992), and therefore, its effect on Braf protein function is unknown.
BRAF	L485_P490del	deletion	gain of function	BRAF L485_P490del results in the deletion of six amino acids within the alphaC-helix region in the protein kinase domain of the Braf protein (PMID: 26732095). L485_P490del confers a gain of function to the Braf protein as demonstrated by increased kinase activity, phosphorylation of downstream Mek and Erk, and transformation ability in cell culture (PMID: 26732095, PMID: 26996308), and is associated with resistance to select RAF inhibitor in cell culture (PMID: 26732095).	Y
BRAF	T488_P492del	deletion	gain of function - predicted	BRAF T488_P492del results in the deletion of five amino acids within the alphaC-helix region in the protein kinase domain of the Braf protein from amino acids 488 to 492 (PMID: 26732095). T488_P492del results in activation of Mek in cell culture (PMID: 26996308), and similar Braf deletions are activating (PMID: 26996308, PMID: 26732095), and therefore, is predicted to lead to a gain of Braf protein function.
BRAF	P490_Q494del	deletion	gain of function - predicted	BRAF P490_Q494del results in the deletion of five amino acids in the protein kinase domain of the Braf protein from amino acids 490 to 494 (PMID: 26732095). P490_Q494del results in activation of Mek in cell culture (PMID: 26996308), and similar Braf deletions are activating (PMID: 26996308, PMID: 26732095), and therefore, is predicted to lead to a gain of Braf protein function.

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Showing 1 to 16 of 16 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF N486_P490del	melanoma	resistant	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Zelboraf (vemurafenib) failed to reduce phosphorylation of Mek and Erk and did not inhibit viability of a melanoma cell line harboring BRAF N486_P490del in culture (PMID: 26996308).	26996308
BRAF N486_P490del	melanoma	sensitive	Cobimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF N486_P490del demonstrated sensitivity to Cotellic (cobimetinib), resulting in decreased cell viability in culture (PMID: 26996308).	26996308
BRAF N486_P490del	ovarian cancer	sensitive	Mirdametinib	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del demonstrated sensitivity to Gomekli (mirdametinib), resulting in decreased cell viability in culture (PMID: 26996308).	26996308
BRAF N486_P490del	ovarian cancer	predicted - sensitive	GDC0879	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del demonstrated partial sensitivity to GDC0879 in culture (PMID: 26996308).	26996308
BRAF N486_P490del	ovarian cancer	resistant	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Zelboraf (vemurafenib) failed to reduce phosphorylation of Mek and Erk and did not inhibit viability of an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 26996308).	26996308
BRAF N486_P490del	ovarian cancer	sensitive	Cobimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del demonstrated sensitivity to Cotellic (cobimetinib), resulting in decreased cell viability in culture (PMID: 26996308).	26996308
BRAF N486_P490del	ovarian cancer	sensitive	AZ628	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del demonstrated sensitivity to AZ628, resulting in decreased cell viability and inhibition of Mek and Erk phosphorylation in culture (PMID: 26996308).	26996308
BRAF N486_P490del	melanoma	sensitive	AZ628	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF N486_P490del demonstrated sensitivity to AZ628, resulting in decreased cell viability and inhibition of Mek and Erk phosphorylation in culture (PMID: 26996308).	26996308
BRAF N486_P490del	melanoma	predicted - sensitive	GDC0879	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF N486_P490del demonstrated partial sensitivity to GDC0879 in culture (PMID: 26996308).	26996308
BRAF N486_P490del	melanoma	sensitive	Mirdametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF N486_P490del demonstrated sensitivity to Gomekli (mirdametinib), resulting in decreased cell viability in culture (PMID: 26996308).	26996308
BRAF N486_P490del BRAF R509H	Advanced Solid Tumor	sensitive	GDC0879	Preclinical - Biochemical	Actionable	In a preclinical study, GDC0879 reduced Mek phosphorylation in transformed cells expressing BRAF N486_P490del and R509H in culture (PMID: 26996308).	26996308
BRAF N486_P490del BRAF R509H	Advanced Solid Tumor	resistant	Vemurafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Zelboraf (vemurafenib) failed to reduce Mek phosphorylation in transformed cells expressing BRAF N486_P490del and R509H in culture (PMID: 26996308).	26996308
BRAF N486_P490del BRAF R509H BRAF V600E	Advanced Solid Tumor	resistant	Vemurafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Zelboraf (vemurafenib) failed to reduce Mek phosphorylation in transformed cells expressing BRAF N486_P490del, V600E, and R509H in culture (PMID: 26996308).	26996308
BRAF N486_P490del BRAF R509H BRAF V600E	Advanced Solid Tumor	sensitive	GDC0879	Preclinical - Biochemical	Actionable	In a preclinical study, GDC0879 reduced Mek phosphorylation in transformed cells expressing BRAF N486_P490del, V600E, and R509H in culture (PMID: 26996308).	26996308
BRAF R509H BRAF V600E	Advanced Solid Tumor	sensitive	GDC0879	Preclinical - Biochemical	Actionable	In a preclinical study, GDC0879 reduced Mek phosphorylation in transformed cells expressing BRAF V600E and R509H in culture (PMID: 26996308).	26996308
BRAF R509H BRAF V600E	Advanced Solid Tumor	sensitive	Vemurafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Zelboraf (vemurafenib) reduced Mek phosphorylation in transformed cells expressing BRAF V600E and R509H in culture (PMID: 26996308).	26996308

Showing 1 to 16 of 16 entries

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