AUTHOR=DuBose Evan , Bevill Samantha M. , Mitchell Dana K. , Sciaky Noah , Golitz Brian T. , Dixon Shelley A. H. , Rhodes Steven D. , Bear James E. , Johnson Gary L. , Angus Steven P. 

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

JOURNAL=Frontiers in Oncology

VOLUME=Volume 14 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1191217

DOI=10.3389/fonc.2024.1191217

ISSN=2234-943X

ABSTRACT=Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN 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 PTEN null to PTEN wild type cells in an isogenic background, CRISPR/Cas9 was used to knock out PTEN in a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 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 PTEN null, BRAFV600E cells. The findings indicate that PTEN null BRAFV600E 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.