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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Oncogene addiction has yielded targeted therapies for lung adenocarcinoma, but RIT1 mutations remain untargeted.
• RIT1 mutations are driver events in ~2% of lung adenocarcinomas, occurring separately from KRAS and EGFR mutations.
• Lack of preclinical models impedes therapeutic development for RIT1-mutant lung cancer.

Purpose of the Study:

• To establish a novel mouse model for RIT1-driven lung cancer.
• To investigate the oncogenic cooperation between RIT1 and other genetic alterations.
• To identify potential therapeutic targets for RIT1-mutant lung cancer.

Main Methods:

• Generated a Cre-regulated mouse model for inducible expression of the human RIT1 M90I variant.
• Assessed cancer development with RIT1 M90I expression alone, with p53 loss, and with Nf2 inactivation.
• Analyzed downstream signaling pathways, including cJUN and YAP/TEAD.
• Evaluated therapeutic efficacy of MEK and YAP/TEAD inhibitors in vivo.

Main Results:

• RIT1 M90I alone or with p53 loss showed weak oncogenic potential.
• Synergy between RIT1 M90I and Nf2 inactivation drove aggressive, highly penetrant lung cancer with rapid onset.
• Oncogenic cooperation was mediated by synergistic activation of cJUN.
• Inhibition of MEK and YAP/TEAD pathways suppressed RIT1-driven lung cancer growth.

Conclusions:

• RIT1 M90I collaborates with Nf2 inactivation to drive aggressive lung cancer via cJUN activation.
• YAP/TEAD signaling is a key mediator of RIT1's oncogenic activity.
• TEAD represents a promising therapeutic target for RIT1-mutant lung cancer.