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|Ref Type||Journal Article|
|Authors||Rajkumar S, Berry D, Heney KA, Strong C, Ramsay L, Lajoie M, Alkallas R, Nguyen TT, Thomson C, Ahanfeshar-Adams M, Dankner M, Petrella T, Rose AAN, Siegel PM, Watson IR|
|Title||Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy.|
|Date||2022 04 05|
|Abstract Text||Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, we reveal that BRAF non-p.V600 mutations co-occurs more frequently with NF1 loss, but not with oncogenic NRAS mutations, than expected by chance. We present cell signaling data, which demonstrate that BRAF non-p.V600 mutants can signal as monomers and dimers within an NF1 loss context. Concordantly, BRAF inhibitors that inhibit both monomeric and dimeric BRAF synergize with MEK inhibition to significantly reduce cell viability in vitro and tumor growth in vivo in BRAF non-p.V600 mutant melanomas with co-occurring NF1 loss-of-function mutations. Our data suggest that patients harboring BRAF non-p.V600 mutant melanomas may benefit from current FDA-approved BRAF/MEK inhibitor combination therapy currently reserved for BRAF p.V600 mutant patients.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
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|BRAF D594G NRAS G12D||melanoma||sensitive||Binimetinib + Encorafenib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Mektovi (binimetinib) and Braftovi (encorafenib) resulted in a synergistic effect in melanoma cells harboring BRAF D594G and NRAS G12D, with decreased cell viability and Erk phosphorylation and increased apoptosis in culture (PMID: 35385748).||35385748|