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April 1st, 2025
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Memorial Sloan Kettering Cancer Center
cancer biology
biorxiv

Loss of Kmt2c/d promotes gastric cancer initiation and confers vulnerability to mTORC1 inhibition and anti-PD1 immunotherapy

Wang, N.Open in Google Scholar•Li, D.Open in Google Scholar•Zhang, T.Open in Google Scholar•Pachai, M. R.Open in Google Scholar•Cho, W. H.Open in Google Scholar•Khudoynazarova, M. N.Open in Google Scholar•Schoeps, D. M.Open in Google Scholar•Bao, Y.Open in Google Scholar•Liu, M.Open in Google Scholar•Tang, L.Open in Google Scholaret al.

KMT2C and KMT2D (KMT2C/D) are frequently mutated in gastric adenocarcinoma, yet their function in cancer initiation remains poorly understood. In this study, based on the observation that loss-of-function mutations of KMT2C and KMT2D are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models to selectively knock out Kmt2c and Kmt2d in gastric epithelial cells with Tmprss2-CreERT2. Through histological staining and single-cell RNA sequencing, we observed that Kmt2c/d loss led to nuclear dysplasia and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks post Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human gastric adenocarcinoma. Kmt2c/d knockout reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering sensitivity to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTROC1 inhibition and anti-PD1 immunotherapy significantly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c/d loss in gastric cancer initiation and suggest the potential therapeutic strategies for KMT2C/D-deficient gastric cancer.

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