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We and others have previously shown that Kras is a much more potent oncogene than oncogenic Nras in hematological malignancies. We attributed the strong leukemogenic activity of Kras at least partially to its unique capability to hyperactivate wild-type (WT) Nras and Hras. Here, we report that Sos1, a guanine nucleotide exchange factor, is required to mediate this process. Sos1 is overexpressed in Kras cells but not in Nras cells. Kras proteins form a complex with Sos1 in vivo. Sos1 deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in Kras cells. Thus, Sos1 deletion ameliorates oncogenic Kras-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of Kras mice. In contrast, Sos1 is dispensable for hyperactivated GM-CSF signaling in Nras cells and Sos1 does not affect MPN phenotypes in Nras mice. Moreover, the survival of Kras; Sos1 recipients is comparable to that of Kras recipients treated with combined MEK and JAK inhibitors. Our study suggests that targeting Sos1-oncogenic Kras interaction may improve the survival of cancer patients with KRAS mutations.
PMID: 30377195 [PubMed - as supplied by publisher]