Abstract 1516: The role of protein tyrosine kinases in DNA mismatch repair

Abstract The DNA mismatch repair (MMR) pathway and its regulation are necessary for genomic stability. Cells deficient in MMR exhibit increased expansion and contraction of short repeat sequences in the genome, termed microsatellite instability (MSI). Loss of MMR also results in resistance to certain classes of DNA damaging chemotherapeutics. The standard treatment option for most patients includes chemotherapy, which has toxic side effects. Immunotherapy has recently been utilized as a treatment for various cancers. MSI-high cancers respond better to immunotherapy treatment compared to microsatellite stable (MSS) cancers. This increased response is believed to be due to the higher mutation frequencies associated with the MSI-high tumors, which lead to greater neoantigen production. The primary proteins required for MMR are known, however regulation of the pathway is not well understood. The MLH1 protein is critical for MMR and is required for the excision licensing of the daughter DNA strand. Loss or mutation of MLH1 leads to defective MMR, increased mutation frequency, and MSI. Recent studies by our laboratory and others have shown that treatment with a tyrosine kinase inhibitor, Imatinib, leads to decreased MLH1 protein expression, and resistance to MMR-dependent apoptosis. These observations suggest a link between Imatinib-sensitive protein tyrosine kinases (PTKs) and the regulation of MMR. We show that MLH1 protein reduction is not occurring at the mRNA level and is thought to be post-transcriptional. We have identified the Imatinib sensitive target most likely responsible for the MLH1 reduction phenotype. We show that the target protein and MLH1 have a physical interaction that likely prevents degradation targeting of MLH1 by the Hsp70 chaperone. A detailed understanding of MMR regulation by PTKs would significantly advance the knowledge in the field of MMR and have important implications for immunotherapy strategies. Citation Format: Hannah Daniels, Breanna Knicely, Eva M. Goellner. The role of protein tyrosine kinases in DNA mismatch repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1516.