Mutation of CMTR2 in Lung Adenocarcinoma Alters RNA Alternative Splicing and Reveals Therapeutic Vulnerabilities

Shigenari Nukaga, Kouya Shiraishi, Kenta Hamabe, Akifumi Mochizuki, Yu Hamaguchi, Emi Ogawa, Nguyen Thai Le, Yoko Shimada, Hanako Ono, Hitomi Nishinakamura, Yoshihisa Kobayashi, Junko Hamamoto, Ayako Ui, Mitsugu Araki, Yukari Sagae, Keiko Ohgino, Kai Sugihara, Satoshi Endo, Jun Miyakoshi, Yuichi Shiraishi, Hiroyuki Yasuda, Yasushi Okuno, Tatsuya Yoshida, Yasushi Goto, Yuichiro Ohe, Shun-Ichi Watanabe, Yasushi Yatabe, Hiroyoshi Nishikawa, Ryuji Hamamoto, Takashi Kohno () and Takashi Nakaoku ()
Additional contact information
Shigenari Nukaga: National Cancer Center Research Institute
Kouya Shiraishi: National Cancer Center Research Institute
Kenta Hamabe: Keio University School of Medicine
Akifumi Mochizuki: National Cancer Center Research Institute
Yu Hamaguchi: National Cancer Center Research Institute
Emi Ogawa: National Cancer Center Research Institute
Nguyen Thai Le: National Cancer Center Research Institute
Yoko Shimada: National Cancer Center Research Institute
Hanako Ono: National Cancer Center Research Institute
Hitomi Nishinakamura: National Cancer Center Research Institute
Yoshihisa Kobayashi: National Cancer Center Research Institute
Junko Hamamoto: Keio University School of Medicine
Ayako Ui: Tohoku University
Mitsugu Araki: Kyoto University
Yukari Sagae: Kyoto University
Keiko Ohgino: Keio University School of Medicine
Kai Sugihara: Kawasaki Municipal Hospital
Satoshi Endo: National Cancer Center Research Institute
Jun Miyakoshi: National Cancer Center Research Institute
Yuichi Shiraishi: National Cancer Center Research Institute
Hiroyuki Yasuda: Keio University School of Medicine
Yasushi Okuno: Kyoto University
Tatsuya Yoshida: National Cancer Center Hospital
Yasushi Goto: National Cancer Center Hospital
Yuichiro Ohe: National Cancer Center Hospital
Shun-Ichi Watanabe: National Cancer Center Hospital
Yasushi Yatabe: National Cancer Center Research Institute
Hiroyoshi Nishikawa: National Cancer Center Research Institute
Ryuji Hamamoto: National Cancer Center Research Institute
Takashi Kohno: National Cancer Center Research Institute
Takashi Nakaoku: National Cancer Center Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract RNA splicing dysregulation has emerged as a hallmark of cancer and a promising therapeutic target; however, its full landscape in human solid cancer remains poorly characterized. To address this, we perform alternative splicing analyses using RNA-sequencing data from 751 lung adenocarcinoma samples from our cohort integrated with 519 samples from The Cancer Genome Atlas. Visualization of splicing patterns using t-distributed stochastic neighbor embedding reveals substantial inter-tumor heterogeneity driven by distinct molecular subtypes and histological differentiation. We identify a unique molecular subtype associated with inactivating mutations in CMTR2, which encodes Cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 2. CMTR2 mutations are observed in 3.8% of cases and are predominantly truncating mutations, which form an isolated cluster within the splicing landscape. Intrinsic and CRISPR-Cas9-engineered CMTR2 mutations disrupt alternative splicing and sensitize cancer cells to sulfonamide-based RNA splicing modulators and immune checkpoint blockade therapy. Retrospective patient data confirm the increased sensitivity of CMTR2-deficient tumors to immune checkpoint blockade therapy. These findings uncover a previously unrecognized RNA splicing deficiency in human cancers and define a molecular subtype of lung adenocarcinoma driven by RNA splicing dysregulation, suggesting targets for therapeutic intervention in lung cancer.

Date: 2025
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DOI: 10.1038/s41467-025-64821-0

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