PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain

查看全文 作　　者：Yamu [1,2]Li;Zhonghua [3]Liu;Yiqing [1,2]Zhao;Jie [3,4,5]Yang;Tsan Sam [3]Xiao;Ronald [1,2]A.Conlon;Zhenghe [1,2]Wang 机构地区：[1]Department of Genetics and Genome Sciences,Case Western Reserve University,Cleveland,OH 44106,USA;[2]Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USA;[3]Department of Pathology,Case Western Reserve University,Cleveland,OH 44106,USA;[4]Department of Physiology and Biophysics,Case Western Reserve University,Cleveland,OH 44106,USA;[5]Department of Integrative Structural and Computational Biology,The Scripps Research Institute,10550 North Torrey Pines Rd,TRY-21,La Jolla,CA 92037,USA. 出　　处：《Genes & Diseases》索引2023年第10卷第4期,共12页 基　　金：supported by the National Institutes of Health(NIH)grants(No.R01CA256791,R01CA264320,P50CA150964,P30CA043703). 摘　　要：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 affin-ity 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-g-induced PD-L1 expres-sion.Mechanistically,ERBB3 regulates IFN-g-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 ki-nase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy,suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune check-point therapy. 关 键 词：Colon cancer ERBB3 IMMUNOTHERAPY PD-L1 Pseudokinase