Unique dependence on Sos1 in Kras^G12D-induced leukemogenesis

We and others have previously shown that Kras^G12D is a much more potent oncogene than oncogenic Nras in hematological malignancies. We attributed the strong leukemogenic activity of Kras^G12D 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^G12D/1 cells, but not in Nras^Q61R/1 and Nras^G12D/+ cells. Kras^G12D proteins form a complex with Sos1 in vivo. Sos1 deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in Kras^G12D/¹ cells. Thus, Sos1 deletion ameliorates oncogenic Kras-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of Kras^G12D/¹ mice. In contrast, Sos1 is dispensable for hyperactivated granulocyte-macrophage colony-stimulating factor signaling in Nras^Q61R/1 cells, and Sos12/2 does not affect MPN phenotypes in Nras^Q61R/1 mice. Moreover, the survival of Kras^G12D/1; Sos12/² recipients is comparable to that of Kras^G12D/1 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.