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

Wang, N.; Li, D.; Zhang, T.; Pachai, M. R.; Cho, W. H.; Khudoynazarova, M. N.; Schoeps, D. M.; Bao, Y.; Liu, M.; Tang, L.; Janjigian, Y.; Chi, P.; Chen, Y.

doi:10.1101/2025.03.27.645747

bioRxiv · 10.1101/2025.03.27.645747

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

Wang, N.·Li, D.·Zhang, T.·Pachai, M. R.·Cho, W. H.·Khudoynazarova, M. N.·Schoeps, D. M.·Bao, Y.·Liu, M.·Tang, L.·Janjigian, Y.·Chi, P.·Chen, Y.

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Abstract

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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Wang, N., Li, D., Zhang, T., Pachai, M. R., Cho, W. H., Khudoynazarova, M. N., Schoeps, D. M., Bao, Y., Liu, M., Tang, L., Janjigian, Y., Chi, P., Chen, Y.. 2025-04-01. Loss of Kmt2c/d promotes gastric cancer initiation and confers vulnerability to mTORC1 inhibition and anti-PD1 immunotherapy. https://doi.org/10.1101/2025.03.27.645747

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