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RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [H2110]

ABSTRACT: RIT1 is a small GTPase of the RAS family and RIT1 mutations have been identified in lung cancer, leukemias, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased levels of this oncoprotein due to impaired proteolysis, resulting in dysregulation of RAS/MAPK and other pathways. Here we document the diversity of RIT1 mutations in human lung cancer and show that physiologic expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Due to the current lack of targeted therapies for this oncoprotein, we undertake different and complementary methods to either inhibit RIT1 directly or the downstream RAS/MAPK pathway. Through a proof-of-concept chemical biology approach, we discover that RAS tri-complex inhibitors bind directly to GTP-bound RIT1 and lead to tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290502 | GEO | 2025/05/08

REPOSITORIES: GEO

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Project description:K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the 'Ras-addiction' of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer. To gain a genome-wide understanding of how MED23 and ELK1 control gene expression in Ras-active lung cancer cells, we performed gene profiling experiments to analyze the transcriptomes from control, si-Med23, or si-Elk1 A549 cells. The si-Ctrl, si-Med23 and si-Elk1 A549 cells were cultured in the normal condition. Then the cells were harvested for RNA extraction and hybridization on Affymetrix microarrays. The analysis contain 9 samples. si-Ctrl cells have three replicates (si-Ctrl#1, si-Ctrl#2 and si-Ctrl#3), and the si-Med23 or si-Elk1 group contains three different cell lines that harbor three different RNAi oligos against Med23 or Elk1 (si-Med23A, B, C and si-Elk1A, B, C).

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RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [H2110]

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