Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition
Naitao Wang, Dan Li, Tao Zhang, Mohini R. Pachai, Dana M. Schoeps, Yudi Bao, Woo Hyun Cho, Makhzuna N. Khudoynazarova, Kae Kristoff, Marion Liu, Laura Tang, Yelena Y. Janjigian, Ping Chi, Yu Chen
Naitao Wang, Dan Li, Tao Zhang, Mohini R. Pachai, Dana M. Schoeps, Yudi Bao, Woo Hyun Cho, Makhzuna N. Khudoynazarova, Kae Kristoff, Marion Liu, Laura Tang, Yelena Y. Janjigian, Ping Chi, Yu Chen
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Research Article Gastroenterology Genetics Oncology

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

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 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.

Authors

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

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Figure 1

Co-occurrence of KMT2C/D LOF mutations and PI3K pathway alterations in STAD.

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Co-occurrence of KMT2C/D LOF mutations and PI3K pathway alterations in S...
(A) OncoPrint of selected chromatin modifying genes and several other large genes in TCGA datasets of STAD from 2014, colorectal adenocarcinoma from 2012, and endometrial adenocarcinoma from 2013. Samples in stomach adenocarcinoma were sorted as MSI, GS, EBV, and CIN groups. Samples in colorectal adenocarcinoma and endometrial adenocarcinoma were sorted as MSI and microsatellite stable (MSS). DMD, dystrophin. (B) Percentage of loss-of-function (LOF) mutations and other mutations in STAD, colorectal adenocarcinoma, and endometrial adenocarcinoma. Splice and nonsense mutations that lead to protein truncations were considered as LOF mutations. (C) Tumor mutational burden in MSI (hypermutated) and MSS (nonhypermutated) cancer samples. The center line represents the median, the box limits represent the upper and lower quartiles, and the minimum and maximum whiskers represent the 10th and 90th percentiles, respectively. (D) Venn diagram showing the overlap of KMT2C and KMT2D LOF mutations in MSI STAD samples. Statistical significance was determined using 2-tailed χ2 test. (E) OncoPrint of KMT2C, KMT2D, and mutations of PI3K signaling (including PTEN, PIK3CA, and PIK3R1). Mutual co-occurrences were observed between pooled mutations of PI3K signaling and KMT2C or KMT2D. Statistical significance was determined using 2-tailed χ2 test.