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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. | ||||||||||||
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| 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. | ||||||||||||
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| 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 select RAF inhibitor in cell culture (PMID: 26732095). | Y |
| 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 | 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 | 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. | |
| 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 | 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 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 | 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 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 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 | 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 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 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 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 | 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 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 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 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 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 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 |