| First Author | Fernández-Pisonero I | Year | 2022 |
| Journal | Cell Rep | Volume | 38 |
| Issue | 11 | Pages | 110522 |
| PubMed ID | 35294890 | Mgi Jnum | J:324845 |
| Mgi Id | MGI:7281969 | Doi | 10.1016/j.celrep.2022.110522 |
| Citation | Fernandez-Pisonero I, et al. (2022) 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 |
| abstractText | 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. |
