Research ArticleCancer

Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation

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Science Signaling  04 Sep 2018:
Vol. 11, Issue 546, eaar8371
DOI: 10.1126/scisignal.aar8371

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Finding alternatives to targeting RAS

Many tumors have mutations in the guanosine triphosphatases (GTPases) HRAS, NRAS, or KRAS. Pharmacologically targeting these proteins has so far been elusive; hence, targeting critical members of their signaling pathway(s) may be more successful. Sheffels et al. found that the guanine nucleotide exchange factor SOS2, in contrast to its family member SOS1, was dispensable for two-dimensional cell proliferation but mediated oncogenic and stem-like switches in the three-dimensional growth behavior of normal and tumor cells to varying degrees, most critically for cells expressing Gly12/13 mutants of KRAS. Further analysis of the differential downstream pathways suggested that SOS2 dependence and RAS mutant type may indicate whether individual inhibitors of the kinase PI3K, AKT, or MEK may be effective against the tumor.