2. Academic Validation
  3. RIT1 Drives Oncogenic Transformation and Is an Actionable Target in Lung Adenocarcinoma

RIT1 Drives Oncogenic Transformation and Is an Actionable Target in Lung Adenocarcinoma

  • Cancer Res. 2025 Sep 2;85(17):3196-3206. doi: 10.1158/0008-5472.CAN-24-3819.
Alessandro M Mozzarelli 1,  Antonio Cuevas-Navarro 2,  Emily G Shuldiner 3,  Martha Vega 1,  Walid K Chatila 4,  Jierui Xu 4,  Henry S Walch 4,  Yuzhe Niu 1,  Dmitri A Petrov 3,  Nikolaus Schultz 4,  Anatoly Urisman 5,  Charles M Rudin 6,  Monte M Winslow 7,  Pau Castel 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, New York.
  • 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 Department of Biology, Stanford University, Stanford, California.
  • 4 Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 5 Department of Pathology, University of California San Francisco, San Francisco, California.
  • 6 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 Department of Genetics, Stanford University School of Medicine, Stanford, California.
PMID: 40644578 DOI: 10.1158/0008-5472.CAN-24-3819
Abstract

RIT1 is a small GTPase of the Ras family, and RIT1 mutations have been identified in lung Cancer, leukemia, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased protein levels due to impaired proteolysis, resulting in dysregulation of Ras/MAPK signaling and Other pathways. In this study, we documented the diversity of RIT1 mutations in human lung Cancer and showed that physiologic expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Evaluation of complementary methods to either inhibit RIT1 directly or the downstream Ras/MAPK pathway revealed that RIT1 M90I tumors are sensitive to SHP2 inhibitors and Ras nucleotide exchange inhibition. Additionally, a proof-of-concept chemical biology approach identified that Ras tri-complex inhibitors bind directly to GTP-bound RIT1, resulting in tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors.

Significance: RIT1 is a bona fide oncogene that promotes lung tumorigenesis and can be directly targeted with Ras tri-complex inhibitors. See related commentary by Wu and Vaishnavi, p. 3186 See related article by DiMarco et al., p. 3207.

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