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Ref Type

Journal Article

PMID

(26732095)

Authors

Chen SH, Zhang Y, Van Horn RD, Yin T, Buchanan S, Yadav V, Mochalkin I, Wong SS, Yue YG, Huber L, Conti I, Henry JR, Starling JJ, Plowman GD, Peng SB

Title

Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	6	3	2016 Mar	300-15	Cancer Discov

URL

Abstract Text

We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer-dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer.

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Showing 1 to 8 of 8 entries

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	M484_N486del	deletion	gain of function - predicted	BRAF M484_N486del results in the deletion of three amino acids within the alphaC-helix region in the protein kinase domain of the Braf protein (PMID: 26732095). M484_N486del has not been characterized, however, is predicted to lead to a gain of protein function due to other characterized BRAF deletions in the same region (PMID: 26732095).
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	N486_L495del	deletion	gain of function - predicted	BRAF N486_L495del results in the deletion of ten amino acids within the alphaC-helix region in the protein kinase domain of the Braf protein (PMID: 26732095). N486_L495del has not been characterized, however, is predicted to lead to a gain of protein function due to other characterized BRAF deletions in the same region (PMID: 26732095).
BRAF	N486_P490del	deletion	gain of function	BRAF N486_P490del 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 486 to 490 (PMID: 26732095). N486_P490del confers a gain of function to the Braf protein as indicated by activation of the MAPK signaling pathway and increased cell proliferation and transformation, and has been demonstrated to confer Braf inhibitor resistance in cell culture (PMID: 37656784, PMID: 26732095).	Y
BRAF	V487_P492delinsA	indel	gain of function	BRAF V487_P492delinsA results in a deletion of six amino acids in the protein kinase domain of the Braf protein from amino acids 487 to 492, combined with the insertion of an alanine (A) at the same site (UniProt.org). V487_P492delinsA results in increased Mek/Erk phosphorylation, cell proliferation and transformation (PMID: 26732095, PMID: 37656784), and confers resistance to select RAF inhibitors in culture (PMID: 37656784).	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	T488_Q493delinsK	indel	gain of function - predicted	BRAF T488_Q493delinsK results in the deletion of six amino acids in the protein kinase domain of the Braf protein from amino acids 488 to 493, combined with the insertion of a lysine (K) at the same site (UniProt.org). T488_Q493delinsK has not been characterized, however, is predicted to lead to a gain of protein function due to other characterized BRAF deletions in the same region (PMID: 26732095).
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 14 of 14 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V487_P492delinsA	pancreatic cancer	resistant	Vemurafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a human pancreatic cancer cell line harboring BRAF V487_P492delinsA was resistant to treatment with Zelboraf (vemurafenib) in both culture and xenograft models (PMID: 26732095).	26732095
BRAF K601N	hematologic cancer	sensitive	LY3009120	Preclinical - Cell culture	Actionable	In a preclinical study, a hematological tumor cell line harboring BRAF K601N demonstrated sensitivity to LY3009120 in culture (PMID: 26732095).	26732095
BRAF L485_P490del	Advanced Solid Tumor	predicted - resistant	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Zelboraf (vemurafenib) failed to inhibit phosphorylation of Mek and Erk in transformed cells expressing BRAF L485_P490del in culture (PMID: 26732095).	26732095
BRAF L485_P490del	Advanced Solid Tumor	predicted - sensitive	LY3009120	Preclinical - Cell culture	Actionable	In a preclinical study, LY3009120 inhibited phosphorylation of Mek and Erk in transformed cells expressing BRAF L485_P490del in culture (PMID: 26732095).	26732095
BRAF N486_P490del	ovarian cancer	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 26732095).	26732095
BRAF L485_P490delinsY	lung non-small cell carcinoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, a non-small cell lung carcinoma cell line harboring BRAF L485_P490delinsY was resistant to Tafinlar (dabrafenib) (PMID: 26732095).	26732095
BRAF L485_P490delinsY	lung non-small cell carcinoma	sensitive	LY3009120	Preclinical	Actionable	In a preclinical study, a non-small cell lung carcinoma cell line harboring BRAF L485_P490delinsY was sensitive to LY3009120 in both culture and xenograft models, resulting in significant tumor regression and inhibition of MEK and ERK phosphorylation (PMID: 26732095).	26732095
BRAF L485_P490delinsY	lung non-small cell carcinoma	sensitive	Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of a non-small cell lung carcinoma cell line harboring BRAF L485_P490delinsY in culture (PMID: 26732095).	26732095
BRAF N486_P490del	ovarian cancer	conflicting	Dabrafenib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) resulted in minimal growth inhibitory activity of an ovarian cancer cell line harboring BRAF N486_P490del (PMID: 26732095).	26732095
BRAF N486_P490del	ovarian cancer	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del was resistant to Zelboraf (vemurafenib), resulting in minimal inhibition of both cell growth and phosphorylation of MEK and ERK in culture (PMID: 26732095).	26732095
BRAF N486_P490del	ovarian cancer	sensitive	LY3009120	Preclinical	Actionable	In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del was sensitive to LY3009120, resulting in inhibition of cell growth and decreased phosphorylation of MEK and ERK in culture (PMID: 26732095).	26732095
BRAF V487_P492delinsA	pancreatic cancer	sensitive	LY3009120	Preclinical	Actionable	In a preclinical study, a pancreatic cancer cell line harboring BRAF V487_P492delinsA were sensitive to LY3009120 in culture and in xenograft models, resulting in inhibition of tumor growth and partial tumor regression (PMID: 26732095).	26732095
BRAF V487_P492delinsA	pancreatic cancer	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, a pancreatic cancer cell line harboring BRAF V487_P492delinsA was resistant to Tafinlar (dabrafenib) (PMID: 26732095).	26732095
BRAF V487_P492delinsA	pancreatic cancer	sensitive	Trametinib	Preclinical	Actionable	In a preclinical study, a pancreatic cancer cell line harboring BRAF V487_P492delinsA was sensitive to Mekinist (trametinib) in culture, resulting in cell growth inhibition (PMID: 26732095).	26732095

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