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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 Cancer discovery
Vol 6
Issue 3
Date 2016 Mar
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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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 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 vemurafenib in cell culture (PMID: 26996308). Y
BRAF L485_P490delinsF indel gain of function - predicted BRAF L485_P490delinsF results in a deletion of six amino acids near the alphaC-helix region of the Braf protein kinase domain combined with the insertion of one new amino acid in the same location (PMID: 26732095). L485_P490delinsF is associated with increased Erk phosphorylation in human tumor samples (PMID: 29544532), and increased activation of MEK/ERK signaling in combination with L485_P490delinsY in cultured cells (PMID: 26732095), and therefore is predicted to confer a gain of function to the Braf protein.
BRAF L485_P490delinsY indel gain of function - predicted BRAF L485_P490delinsY results in a deletion of six amino acids near the alphaC-helix region of the Braf protein kinase domain combined with the insertion of one new amino acid in the same location (PMID: 26732095). L485_P490delinsY is associated with increased MEK/ERK activation in cells also harboring L485_P490delinsF, and similar deletions result in Braf activation (PMID: 26732095), and therefore, L485_P490delinsY is predicted to confer a gain of function to the Braf protein.
BRAF L485_Q494del deletion gain of function - predicted BRAF L485_Q494del results in the deletion of ten amino acids within the alphaC-helix region in the protein kinase domain of the Braf protein (PMID: 26732095, UniProt.org). L485_Q494del has not been characterized, however, is predicted to result in a gain of 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 near the alphaC-helix region of the kinase domain (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 in culture (PMID: 26732095).
BRAF P490_Q494del deletion gain of function - predicted BRAF P490_Q494del results in the deletion of five amino acids near the alphaC-helix region of the protein kinase domain in 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 P490_Q494del is predicted to confer a gain of function to the Braf function.
BRAF T488_P492del deletion gain of function - predicted BRAF T488_P492del results in the deletion of five amino acids near the alphaC-helix region of the protein kinase domain in 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 T488_P492del is predicted to confer a gain of function to the Braf function.
BRAF T488_Q493delinsK indel gain of function - predicted BRAF T488_Q493delinsK results in the deletion of six amino acids near the alphaC-helix region of the Braf protein kinase domain combined with the insertion of one new amino acid in the same location (PMID: 26732095). T488_Q493delinsK has not been characterized, however, is predicted to result in a gain of function due to other characterized BRAF deletions in the same region (PMID: 26732095).
BRAF V487_P492delinsA indel gain of function BRAF V487_P492delinsA results in a deletion of six amino acids near the alphaC-helix region of the kinase domain of the Braf protein combined with the insertion of one new amino acid in the same location (PMID: 26732095). V487_P492delinsA confers a gain of function to the Braf protein as indicated by increased pathway signaling and cell proliferation in culture (PMID: 26732095).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 L485_P490delinsY lung non-small cell carcinoma sensitive Trametinib Preclinical Actionable In a preclinical study, a non-small cell lung carcinoma cell line harboring BRAF L485_P490delinsY was sensitive to Mekinist (trametinib), resulting in cell growth inhibition (PMID: 26732095). 26732095
BRAF N486_P490del ovarian cancer predicted - resistant 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 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 N486_P490del ovarian cancer sensitive Trametinib Preclinical Actionable In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del was sensitive to Mekinist (trametinib), resulting in inhibition of cell growth in culture (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
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 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 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 L485_P490delinsY lung non-small cell carcinoma resistant Vemurafenib 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