How PD-L1 expression is regulated in
cancer is poorly understood. Here, we report that the
ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in
colorectal cancers (
CRCs). ERBB3 is one of the four members of the
EGF receptor family, all with
protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to
ATP. We showed that ERBB3
ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft
tumor growth of CRC cell lines. The ERBB3
ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the
transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a
tumor-derived ERBB3 mutation located in the
kinase domain sensitizes mouse
colon cancers to anti-PD1 antibody
therapy, suggesting that ERBB3 mutations could be predictive
biomarkers for
tumors amenable to immune checkpoint
therapy.