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=14

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=<sec><title>Introduction</title><p>Approximately 50% of melanomas harbor an activating <italic>BRAFV600E</italic> mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. <italic>PTEN</italic> 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.</p></sec><sec><title>Methods</title><p>To compare the response of <italic>PTEN</italic> null to <italic>PTEN</italic> wild-type cells in an isogenic background, CRISPR/Cas9 was used to knock out <italic>PTEN</italic> in a melanoma cell line that harbors a <italic>BRAFV600E</italic> mutation. RNA sequencing, functional kinome analysis, and drug synergy screening were employed in the context of BRAF/MEK inhibition.</p></sec><sec><title>Results</title><p>RNA sequencing and functional kinome analysis revealed that the loss of PTEN led to an induction of <italic>FOXD3</italic> and an increase in expression of the FOXD3 target gene, <italic>ERBB3/HER3</italic>. Inhibition of BRAF and MEK1/2 in <italic>PTEN</italic> null, <italic>BRAFV600E</italic> cells dramatically induced the expression of <italic>ERBB3/HER3</italic> 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 <italic>PTEN</italic> null, <italic>BRAFV600E</italic> cells.</p></sec><sec><title>Conclusions</title><p>The findings indicate that <italic>PTEN</italic> null <italic>BRAFV600E</italic> 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.</p></sec>