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ResearchIn-Press PreviewGastroenterologyGeneticsOncology Open Access | 10.1172/JCI194462

Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD1 inhibition

Naitao Wang,1 Dan Li,1 Tao Zhang,1 Mohini R. Pachai,1 Dana M. Schoeps,1 Yudi Bao,1 Woo Hyun Cho,1 Makhzuna N. Khudoynazarova,1 Kae Kristoff,1 Marion Liu,1 Laura Tang,1 Yelena Y. Janjigian,2 Ping Chi,1 and Yu Chen1

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Tang, L. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Janjigian, Y. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Chi, P. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Chen, Y. in: PubMed | Google Scholar |

Published May 12, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI194462.
Copyright © 2026, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 12, 2026 - Version history
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Abstract

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 model (GEMM) 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 post 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 shows co-clustering 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 to be hypersensitive to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTORC1 inhibition and anti-PD1 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 the potential therapeutic strategies for KMT2C/D-deficient gastric cancer.

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  • Version 1 (May 12, 2026): In-Press Preview
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