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

The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma, but many rare driver mutations remain untargeted. Somatic mutations of the “Ras-like in all tissues” (RIT1) gene are non-canonical driver events in lung cancer, occurring in ~2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1-mutant lung cancer. Here we report a new mouse model with inducible regulation of the cancer-associated RIT1M90I variant. We show that autochthonous expression of RIT1M90I in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1M90I and inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1M90I-driven lung cancer in vitro and in vivo. These data identify YAP/TEAD as an important mediator of RIT1’s oncogenic potential and nominate TEAD as an important drug target in RIT1-mutant lung cancer.