Key Points

  • Sos1 mediates oncogenic Kras-induced WT Nras and Hras hyperactivation.

  • Sos1−/− attenuates KrasG12D-induced MPN and prolongs the survival of KrasG12D mice.

Abstract

We and others have previously shown that KrasG12D is a much more potent oncogene than oncogenic Nras in hematological malignancies. We attributed the strong leukemogenic activity of KrasG12D 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 KrasG12D/+ cells, but not in NrasQ61R/+ and NrasG12D/+ cells. KrasG12D proteins form a complex with Sos1 in vivo. Sos1 deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in KrasG12D/+ cells. Thus, Sos1 deletion ameliorates oncogenic Kras-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of KrasG12D/+ mice. In contrast, Sos1 is dispensable for hyperactivated granulocyte-macrophage colony-stimulating factor signaling in NrasQ61R/+ cells, and Sos1−/− does not affect MPN phenotypes in NrasQ61R/+ mice. Moreover, the survival of KrasG12D/+; Sos1−/− recipients is comparable to that of KrasG12D/+ 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.

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