Role of Erbb3 kinase activity in colorectal tumorigenesis.

ABSTRACT Immunotherapy is the standard of care and an effective treatment for colorectal cancers with deficient mismatch repair proteins (dMMR). The deficiency contributes to high tumor mutational burden in the tumors and the generation of neoantigens that can activate the immune system. However, despite the effectiveness of

immunotherapy for dMMR colorectal cancers, up to half of patients with dMMR cancers do not derive clinical benefit from the treatment. Intrinsic or acquired resistance to immunotherapy may limit clinical efficacy and thus a better understanding of the factors and mechanisms that lead to resistance is needed. The growing

interest in using immunotherapy in the neoadjuvant setting for dMMR tumors further underscores the need to prevent or limit resistance to immunotherapy. Tumor intrinsic factors and mechanisms related to molecular alterations and changes in signaling pathways likely contribute to pre-existing and acquired immunotherapy

resistance. Targeting tumor-intrinsic mechanisms in combination with immunotherapy may improve overall survival of patients with dMMR colorectal cancers. Our main goal for this study is to identify and validate genes and signaling pathways associated with resistance to immunotherapy in dMMR colorectal cancer using a

mouse model and gene-editing tools. We will validate a select set of genes most likely to play a role in resistance to immunotherapy. In the long term, data from this project will guide our efforts to determine the mechanisms of immunotherapy resistance and to design highly effective combination therapies that either

anticipate or limit the development of resistance to immunotherapy.