Neratinib, a pan ERBB/HER inhibitor, restores sensitivity of PTEN -null, BRAFV600E melanoma to BRAF/MEK inhibition

Approximately 50% of melanomas harbor an activating mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. loss-of-function mutations occur in ~40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of null to wild-type cells in an isogenic background, CRISPR/Cas9 was used to knock out in a melanoma cell line that harbors a mutation. RNA sequencing, functional kinome analysis, and drug synergy screening were employed in the context of BRAF/MEK inhibition. RNA sequencing and functional kinome analysis revealed that the loss of PTEN led to an induction of and an increase in expression of the FOXD3 target gene, . Inhibition of BRAF and MEK1/2 in null, cells dramatically induced the expression of relative to wild-type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi revealed that the pan ERBB/HER inhibitor, neratinib, could reverse the resistance observed in null, cells. The findings indicate that null melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of BRAFi/MEKi resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.