Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

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.
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.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
BRAF L597S LY3009120
BRAF G596R LY3009120
BRAF G464V LY3009120
BRAF L597V LY3009120
BRAF L505H LY3009120
BRAF A728V LY3009120
BRAF G469V LY3009120
BRAF S467A LY3009120
BRAF L485_P490del LY3009120
BRAF T488_P492del LY3009120
BRAF F247L LY3009120
BRAF K601E LY3009120
BRAF F468C LY3009120
BRAF D594_T599dup LY3009120
BRAF I463S LY3009120
BRAF G596D LY3009120
BRAF T599I LY3009120
BRAF K601T LY3009120
BRAF G469R LY3009120
BRAF N486_L495del LY3009120
BRAF G596C LY3009120
BRAF Q257R LY3009120
BRAF L597R LY3009120
BRAF T599_V600insEAT LY3009120
BRAF V487_P492delinsA LY3009120
BRAF M484_N486del LY3009120
BRAF K499E LY3009120
BRAF N486_P490del LY3009120
BRAF L485F LY3009120
BRAF G469S LY3009120
BRAF G464R LY3009120
BRAF K601N LY3009120
BRAF T599_V600insETT LY3009120
BRAF G469A LY3009120
BRAF V504_R506dup LY3009120
BRAF G596V LY3009120
BRAF L485_P490delinsF LY3009120
BRAF T599R LY3009120
BRAF V600_K601delinsE LY3009120
BRAF L597P LY3009120
BRAF L485_P490delinsY LY3009120
BRAF G469del LY3009120
BRAF V471F LY3009120
BRAF G464E LY3009120
BRAF G466R LY3009120
BRAF T488_Q493delinsK LY3009120
BRAF V600dup LY3009120
BRAF A598V LY3009120
BRAF G469L LY3009120
BRAF A598_T599insARC LY3009120
BRAF P490_Q494del LY3009120
BRAF K601I LY3009120
BRAF E586K LY3009120
BRAF T599dup LY3009120
BRAF G466V LY3009120
BRAF act mut LY3009120
BRAF V600delinsYM LY3009120
BRAF L597Q LY3009120
BRAF A598_T599insV LY3009120
BRAF T599_V600insTT LY3009120
BRAF R347* LY3009120
BRAF K601Q LY3009120
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 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 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 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_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 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 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_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 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 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_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 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