Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mutations in Ras-like in all tissues (RIT1) are found in lung adenocarcinomas.
• RIT1 mutations are mutually exclusive with KRAS and EGFR mutations, suggesting a distinct oncogenic role.
• A lack of RIT1-mutant lung cancer models impedes therapeutic development.

Purpose of the Study:

• To create and characterize a mouse model for RIT1-mutant lung cancer.
• To investigate the oncogenic mechanisms driven by RIT1 mutations.
• To identify potential therapeutic targets for RIT1-driven lung cancer.

Main Methods:

• Generated a mouse model with conditional expression of the RIT1 M90I variant.
• Combined RIT1 M90I expression with Nf2 and p53 inactivation.
• Analyzed lung cancer development, penetrance, and latency.
• Investigated downstream signaling pathways, including AP-1 and YAP/TEAD.
• Tested the efficacy of MEK and TEAD inhibition.

Main Results:

• Autochthonous RIT1 M90I expression with Nf2/p53 loss induced aggressive lung cancer with 100% penetrance.
• Oncogenic cooperation was linked to synergistic activation of AP-1 transcription factors.
• YAP/TEAD signaling was identified as a mediator of RIT1's oncogenic function.
• Combined MEK and TEAD inhibition reversed oncogenic phenotypes.

Conclusions:

• A novel mouse model for RIT1-mutant lung cancer has been established.
• RIT1 acts as a non-canonical driver oncogene in lung cancer, cooperating with p53/Nf2 loss.
• YAP/TEAD pathway is crucial for RIT1-driven oncogenesis.
• Targeting TEAD presents a potential therapeutic strategy for RIT1-mutant lung cancer.