A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors
Isabel Fernández‐Pisonero, Laura Clavaín, Javier Robles‐Valero, L. Francisco Lorenzo‐Martín, Rubén Caloto, Blanca Nieto, Carmen García-Macías, Clara L. Oeste, Manuel Sánchez‐Martín, Antonio Abad, Alejandro M. Hortal, Dolores Caballero, Marcos González, Mercedes Dosil, Balbino Alarcón, Xosé R. Bustelo
Abstract
A missense change in RRAS2 (Gln 72 to Leu), analogous to the Gln 61 -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-Ras2 Q72L 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-Ras2 Q72L -driven tumors can be classified into different subtypes according to therapeutic susceptibility. Importantly, the most relevant R-Ras2 Q72L -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-Ras2 Q72L of pathways that orthogonally stimulate mTORC1 signaling. These findings demonstrate that RRAS2 Q72L is a bona fide oncogenic driver and unveil therapeutic strategies for patients with cancer and Noonan syndrome bearing RRAS2 mutations.