Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition.

Based on the observation that loss-of-function mutations of KMT2C and KMT2D (KMT2C/D) are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models (GEMMs) to conditionally knock out Kmt2c and Kmt2d in gastric epithelial cells. We observed that Kmt2c/d loss led to nuclear dysplasia, cellular crowding, 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 after Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human intestinal-type gastric adenocarcinoma. Bioinformatic integration of single-cell RNA-seq of our GEMMs and human gastric cancer datasets showed coclustering of normal and of cancerous gastric epithelial cells. Kmt2c/d knockout in gastric epithelium reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering the cells hypersensitive to mTOR complex 1 (mTORC1) inhibitors. Additionally, Kmt2c/d knockout increased MHC class I molecule expression and enhanced antigen presentation. Combination of mTORC1 inhibition and anti-programmed cell death 1 immunotherapy markedly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c/d loss in gastric cancer initiation and suggest potential therapeutic strategies for KMT2C/D-deficient gastric cancer.