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

Mutations in "Ras-like in all tissues" (RIT1) occur in up to 2% of lung adenocarcinomas and are mutually exclusive with KRAS and EGFR mutations, suggesting that RIT1 may act as a non-canonical driver oncogene in lung cancer. However, the lack of a RIT1-mutant lung cancer model has hindered the development and testing of RIT1-targeted therapeutics. Here, we report a mouse model with conditional regulation of the cancer-associated RIT1<sup>M90I</sup> variant. We show that autochthonous expression of RIT1<sup>M90I</sup> and combined inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. Oncogenic cooperation between RIT1<sup>M90I</sup> and p53/Nf2 loss is driven by synergistic activation of AP-1 transcription factors and can be reversed by the combined inhibition of MEK and TEAD. These data identify YAP/TEAD as a mediator of RIT1's oncogenic capability and nominate TEAD as a potential drug target in RIT1-mutant lung cancer.

Authors

Institutions

Publication Details

Journal
Cell Reports
Published
2025-09-25
DOI
https://doi.org/10.1016/j.celrep.2025.116185
Citations
1
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
1.15
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Mark B. Headley, Feinan Wu, April Lo, Fujiko Duke et al.
1 citations
Cell Reports
Hippo pathway signaling and YAP/TAZ
1.15
article

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

Mark B. Headley, Feinan Wu, April Lo, Fujiko Duke, Andrew Lowe, Maria McSharry, Siobhan O’Brien, Saksham Gupta, Raisa Glabman, Amanda Koehne, Marga B. Rominger, Shriya Kamlapurkar, Sitapriya Moorthi, Elizabeth Cromwell, Annie Waldum
article en
1 citations

Abstract

Mutations in "Ras-like in all tissues" (RIT1) occur in up to 2% of lung adenocarcinomas and are mutually exclusive with KRAS and EGFR mutations, suggesting that RIT1 may act as a non-canonical driver oncogene in lung cancer. However, the lack of a RIT1-mutant lung cancer model has hindered the development and testing of RIT1-targeted therapeutics. Here, we report a mouse model with conditional regulation of the cancer-associated RIT1<sup>M90I</sup> variant. We show that autochthonous expression of RIT1<sup>M90I</sup> and combined inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. Oncogenic cooperation between RIT1<sup>M90I</sup> and p53/Nf2 loss is driven by synergistic activation of AP-1 transcription factors and can be reversed by the combined inhibition of MEK and TEAD. These data identify YAP/TEAD as a mediator of RIT1's oncogenic capability and nominate TEAD as a potential drug target in RIT1-mutant lung cancer.

Cell ReportsVol. 44(10)
Broad Institute (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Fred Hutch Cancer Center (US)
Openalex Percentile: Top 19%
Hippo pathway signaling and YAP/TAZ
1.15
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.