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Ref Type Journal Article
PMID (37656784)
Authors Lauinger M, Christen D, Klar RFU, Roubaty C, Heilig CE, Stumpe M, Knox JJ, Radulovich N, Tamblyn L, Xie IY, Horak P, Forschner A, Bitzer M, Wittel UA, Boerries M, Ball CR, Heining C, Glimm H, Fröhlich M, Hübschmann D, Gallinger S, Fritsch R, Fröhling S, O'Kane GM, Dengjel J, Brummer T
Title BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability.
Journal Vol Issue Date Pages Journal Short Title
Science advances 9 35 2023 Sep eade7486 Sci Adv
URL
Abstract Text In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAFΔβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAFΔβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAFΔLNVTAP>F and two novel mutants, BRAFdelinsFS and BRAFΔLNVT>F, and compare them with other BRAFΔβ3-αC oncoproteins. We show that BRAFΔβ3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAFΔβ3-αC oncoproteins, e.g., BRAFΔLNVTAP>F, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAFΔβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.

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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 L485_P490delinsF indel gain of function BRAF L485_P490delinsF results in a deletion of six amino acids in the protein kinase domain of the Braf protein from amino acids 485 to 490, combined with the insertion of a phenylalanine (F) at the same site (UniProt.org). L485_P490delinsF results in increased Mek/Erk phosphorylation, is transforming, and is associated with resistance to select RAF inhibitors in culture (PMID: 37656784). Y
BRAF L485_P490delinsFS indel gain of function BRAF L485_P490delinsFS results in a deletion of six amino acids in the protein kinase domain of the Braf protein from amino acids 485 to 490, combined with the insertion of a phenylalanine (F) and a serine (S) at the same site (UniProt.org). L485_P490delinsY results in increased Mek/Erk phosphorylation, is transforming, and is associated with resistance to select RAF inhibitors in culture (PMID: 37656784). Y
BRAF L485_P490delinsY indel gain of function BRAF L485_P490delinsY results in a deletion of six amino acids in the protein kinase domain of the Braf protein from amino acids 485 to 490, combined with the insertion of a tyrosine (Y) at the same site (UniProt.org). L485_P490delinsY results in increased Mek/Erk phosphorylation, is transforming, and is associated with resistance to select RAF inhibitors in culture (PMID: 37656784). Y
BRAF L485_T488delinsF indel gain of function - predicted BRAF L485_T488delinsF results in a deletion of four amino acids in the protein kinase domain of the Braf protein from amino acids 485 to 488, combined with the insertion of a phenylalanine (F) at the same site (UniProt.org). L485_T488delinsF 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: 37656784).
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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF N486_P490del Advanced Solid Tumor predicted - sensitive Trametinib Preclinical - Biochemical Actionable In a preclinical study, Mekinist (trametinib) inhibited Mek and Erk phosphorylation in cells expressing BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA Advanced Solid Tumor predicted - sensitive Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited Mek and Erk phosphorylation in cells expressing BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF N486_P490del pancreatic ductal adenocarcinoma sensitive LXH 254 Preclinical - Patient cell culture Actionable In a preclinical study, LXH 254 inhibited growth of organoids derived from pancreatic ductal adenocarcinoma patients harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF N486_P490del pancreatic ductal adenocarcinoma sensitive Sorafenib Preclinical - Patient cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited growth of organoids derived from pancreatic ductal adenocarcinoma patients harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive Trametinib Preclinical - Biochemical Actionable In a preclinical study, Mekinist (trametinib) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive Sorafenib Preclinical - Biochemical Actionable In a preclinical study, Nexavar (sorafenib) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited colony formation in a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA Advanced Solid Tumor predicted - sensitive LXH 254 Preclinical - Biochemical Actionable In a preclinical study, LXH 254 inhibited Mek and Erk phosphorylation in cells expressing BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive Lifirafenib Preclinical - Biochemical Actionable In a preclinical study, Lifirafenib (BGB-283) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsF Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsF in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY Advanced Solid Tumor predicted - resistant Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, Tafinlar (dabrafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive GDC0879 Preclinical - Biochemical Actionable In a preclinical study, GDC-0879 inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY Advanced Solid Tumor predicted - sensitive Trametinib Preclinical - Biochemical Actionable In a preclinical study, Mekinist (trametinib) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer predicted - sensitive LXH 254 + Trametinib Preclinical - Biochemical Actionable In a preclinical study, combination of Mekinist (trametinib) and LXH 254 resulted in enhanced inhibition of metabolic activity in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY Advanced Solid Tumor predicted - sensitive LXH 254 Preclinical - Biochemical Actionable In a preclinical study, LXH 254 inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsF Advanced Solid Tumor predicted - sensitive Trametinib Preclinical - Biochemical Actionable In a preclinical study, Mekinist (trametinib) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsF in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma sensitive LXH 254 Preclinical - Cell culture Actionable In a preclinical study, LXH 254 inhibited MAPK signaling and colony formation in a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF N486_P490del pancreatic ductal adenocarcinoma sensitive Trametinib Preclinical - Patient cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of organoids derived from pancreatic ductal adenocarcinoma patients harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF N486_P490del Advanced Solid Tumor predicted - sensitive LXH 254 Preclinical - Biochemical Actionable In a preclinical study, LXH 254 inhibited Mek and Erk phosphorylation in cells expressing BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive TAK-632 Preclinical - Biochemical Actionable In a preclinical study, TAK-632 inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - resistant Encorafenib Preclinical - Biochemical Actionable In a preclinical study, Braftovi (encorafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer predicted - sensitive Sorafenib + Trametinib Preclinical - Biochemical Actionable In a preclinical study, combination of Mekinist (trametinib) and Nexavar (sorafenib) resulted in enhanced inhibition of metabolic activity in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - resistant Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, Tafinlar (dabrafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma sensitive LXH 254 Preclinical - Cell culture Actionable In a preclinical study, LXH 254 inhibited MAPK signaling and colony formation in a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited MAPK signaling and colony formation in a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF L485_T488delinsF Advanced Solid Tumor predicted - resistant Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L485_T488delinsF were resistant to Tafinlar (dabrafenib)-induced inhibition of ERK and MEK signaling in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsF Advanced Solid Tumor predicted - resistant Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, Tafinlar (dabrafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsF in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer conflicting Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited MAPK signaling and colony formation in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma predicted - sensitive Ulixertinib Preclinical - Biochemical Actionable In a preclinical study, Ulixertinib (BVD-523) inhibited metabolic activity in a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma predicted - sensitive Ulixertinib Preclinical - Biochemical Actionable In a preclinical study, Ulixertinib (BVD-523) inhibited metabolic activity in a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma predicted - sensitive Sorafenib + Trametinib Preclinical - Biochemical Actionable In a preclinical study, combination of Mekinist (trametinib) and Nexavar (sorafenib) resulted in enhanced inhibition of metabolic activity in a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA Advanced Solid Tumor predicted - sensitive Trametinib Preclinical - Biochemical Actionable In a preclinical study, Mekinist (trametinib) inhibited Mek and Erk phosphorylation in cells expressing BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF N486_P490del pancreatic ductal adenocarcinoma sensitive SCH772984 Preclinical - Patient cell culture Actionable In a preclinical study, SCH772984 inhibited growth of organoids derived from pancreatic ductal adenocarcinoma patients harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_T488delinsF Advanced Solid Tumor predicted - sensitive Sorafenib Preclinical - Biochemical Actionable In a preclinical study, Nexavar (sorafenib) inhibited ERK and MEK signaling in cells expressing BRAF L485_T488delinsF in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma predicted - sensitive LXH 254 + Trametinib Preclinical - Biochemical Actionable In a preclinical study, combination of Mekinist (trametinib) and LXH 254 resulted in enhanced inhibition of metabolic activity in a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer predicted - sensitive Ulixertinib Preclinical - Biochemical Actionable In a preclinical study, Ulixertinib (BVD-523) inhibited metabolic activity in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsF Advanced Solid Tumor predicted - sensitive LXH 254 Preclinical - Biochemical Actionable In a preclinical study, LXH 254 inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsF in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma predicted - sensitive Sorafenib + Trametinib Preclinical - Biochemical Actionable In a preclinical study, combination of Mekinist (trametinib) and Nexavar (sorafenib) resulted in enhanced inhibition of metabolic activity in a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma decreased response Encorafenib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY was less sensitive to Braftovi (encorafenib) treatment compared to type II RAF inhibitors in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer decreased response Encorafenib Preclinical - Cell culture Actionable In a preclinical study, an ovarian cancer cell line harboring BRAF N486_P490del was less sensitive to Braftovi (encorafenib) treatment compared to type II RAF inhibitors in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY Advanced Solid Tumor predicted - resistant Encorafenib Preclinical - Biochemical Actionable In a preclinical study, Braftovi (encorafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited MAPK signaling and colony formation in a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited colony formation in a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsF Advanced Solid Tumor predicted - resistant Encorafenib Preclinical - Biochemical Actionable In a preclinical study, Braftovi (encorafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsF in culture (PMID: 37656784). 37656784
BRAF V487_P492delinsA pancreatic carcinoma decreased response Encorafenib Preclinical - Cell culture Actionable In a preclinical study, a pancreatic carcinoma cell line harboring BRAF V487_P492delinsA was less sensitive to Braftovi (encorafenib) treatment compared to type II RAF inhibitors in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer sensitive LXH 254 Preclinical - Cell culture Actionable In a preclinical study, LXH 254 inhibited MAPK signaling and colony formation in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF N486_P490del pancreatic ductal adenocarcinoma sensitive Binimetinib Preclinical - Patient cell culture Actionable In a preclinical study, Mektovi (binimetinib) inhibited growth of organoids derived from pancreatic ductal adenocarcinoma patients harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF N486_P490del Advanced Solid Tumor predicted - sensitive Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited Mek and Erk phosphorylation in cells expressing BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited colony formation in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsY lung non-small cell carcinoma predicted - sensitive LXH 254 + Trametinib Preclinical - Biochemical Actionable In a preclinical study, combination of Mekinist (trametinib) and LXH 254 resulted in enhanced inhibition of metabolic activity in a non-small cell lung cancer cell line harboring BRAF L485_P490delinsY in culture (PMID: 37656784). 37656784
BRAF N486_P490del ovarian cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited MAPK signaling and colony formation in an ovarian cancer cell line harboring BRAF N486_P490del in culture (PMID: 37656784). 37656784
BRAF L485_T488delinsF Advanced Solid Tumor predicted - sensitive LXH 254 Preclinical - Biochemical Actionable In a preclinical study, LXH 254 inhibited ERK and MEK signaling in cells expressing BRAF L485_T488delinsF in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive Belvarafenib Preclinical - Biochemical Actionable In a preclinical study, Belvarafenib (HM95573) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive Tovorafenib Preclinical - Biochemical Actionable In a preclinical study, Ojemda (tovorafenib) inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF L485_P490delinsFS Advanced Solid Tumor predicted - sensitive LXH 254 Preclinical - Biochemical Actionable In a preclinical study, LXH 254 inhibited Mek and Erk phosphorylation in cells expressing BRAF L485_P490delinsFS in culture (PMID: 37656784). 37656784
BRAF N486_P490del Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit Mek and Erk phosphorylation in cells expressing BRAF N486_P490del in culture (PMID: 37656784). 37656784