The overarching goals of this proposal are to determine if Erbb3 kinase plays a critical role in colorectal tumorigenesis and to test if colorectal cancer with oncogenic Erbb3 mutations respond better to anti-PD1 antibody. Erbb3, a member of the EGFR family of receptor protein tyrosine kinases, is mutated in a variety of human cancers including colorectal cancer (CRC). Unlike other EGFR family members, the kinase domain of Erbb3 is thought to be a pseudo-kinase without enzymatic activity. Although it is well documented that Erbb3 plays an oncogenic role in tumorigenesis, the mechanisms by which Erbb3 activation drives tumorigenesis are largely unknown. We made the paradigm-shifting discovery that the pseudo-kinase domain of Erbb3 is a serine/threonine (S/T) kinase activated by phosphorylation of a serine site in the juxatomembrane domain, and that its kinase activity is required for robust tumor growth in both xenograft and genetically engineered mouse models. Moreover, we found that a Erbb3 kinase-dead mutant impairs interferon-γ (IFN-γ)-induced PD-L1 expression in CRCs. Interestingly, knockin of an oncogenic Erbb3 mutation in mouse colon cancer cell lines renders them sensitive to anti-PD1 antibody therapy. Here we propose two aims to determine the role of Erbb3 S/T kinase in (1) colorectal tumorigenesis and (2) the response of colorectal cancers to immune checkpoint inhibitors. Successful completion of our proposed studies will lay a solid foundation for targeting Erbb3 mutant CRCs with Erbb3 kinase inhibitors and/or immune checkpoint inhibitors. Given that aberrant activation of Erbb3 causes resistance to various cancer therapies including Herceptin in breast cancer and EGFR inhibitors in lung cancer, the impact of our studies will have a broad impact on cancer therapy.