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.
Publications
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Article type
Year
Open Access
Full Length Article
Issue
Genes & Diseases 2023, 10 (4): 1702-1713
Published: 08 December 2022
Downloads:7
Open Access
View on News
Issue
Genes & Diseases 2018, 5 (4): 301
Published: 20 November 2018
Downloads:1
Open Access
Commentary
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Genes & Diseases 2016, 3 (4): 241-243
Published: 10 September 2016
Downloads:2
We recently reported that PIK3CA mutant colorectal cancers (CRCs) are addicted to glutamine through up-regulation of glutamate pyruvate transaminase 2 (GPT2). A GPT2 inhibitor suppresses in vivo growth of PIK3CA mutant, but not wild-type, CRCs. This study indicates that targeting glutamine may be an effective approach to treat CRCs with PIK3CA mutations.
Total 3