A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors.
Cell Rep
; 38(11): 110522, 2022 03 15.
Article
en En
| MEDLINE
| ID: mdl-35294890
ABSTRACT
A missense change in RRAS2 (Gln72 to Leu), analogous to the Gln61-to-Leu mutation of RAS oncoproteins, has been identified as a long-tail hotspot mutation in cancer and Noonan syndrome. However, the relevance of this mutation for in vivo tumorigenesis remains understudied. Here we show, using an inducible knockin mouse model, that R-Ras2Q72L triggers rapid development of a wide spectrum of tumors when somatically expressed in adult tissues. These tumors show limited overlap with those originated by classical Ras oncogenes. R-Ras2Q72L-driven tumors can be classified into different subtypes according to therapeutic susceptibility. Importantly, the most relevant R-Ras2Q72L-driven tumors are dependent on mTORC1 but independent of phosphatidylinositol 3-kinase-, MEK-, and Ral guanosine diphosphate (GDP) dissociation stimulator. This pharmacological vulnerability is due to the extensive rewiring by R-Ras2Q72L of pathways that orthogonally stimulate mTORC1 signaling. These findings demonstrate that RRAS2Q72L is a bona fide oncogenic driver and unveil therapeutic strategies for patients with cancer and Noonan syndrome bearing RRAS2 mutations.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Unión al GTP Monoméricas
/
Síndrome de Noonan
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article