The PI3K Inhibitor GDC-0941 Attenuates Disease in a KrasG12D Mouse Model of CMML and JMML

Abstract 2862 Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are overlap myelodysplastic/myeloproliferative neoplasia (MDS/MPN) syndromes that respond poorly to conventional treatment regimens. Both diseases are characterized by aberrant N-Ras, K-Ras, Cbl, and SHP-2 proteins, which are not attractive drug target candidates. Focus has shifted to downstream effector pathways, which include Raf/MEK/ERK, phosphoinositide-3-OH kinase (PI3K)/Akt, and Ral-GDS/Ral-A cascades. However, it is unclear which pathways, if any, should be targeted. In part to address this question, we previously developed a mouse model of CMML and JMML by expressing a conditional “knock-in” KrasG12D oncogene in bone marrow. Our earlier studies showed that inhibition of MEK yields a significant reduction in disease burden in this model, including reduced leukocytosis, improved anemia and enhanced survival. Here, we interrogate the role of the PI3K/Akt pathway in KrasG12D driven MPN and further explore which specific pathways are responsible for leukemogenesis due to hyperactive Ras. We administered GDC-0941, a selective PI3K inhibitor, to Mx1-Cre, KrasG12D mutant mice Mice with well established MPN and wild-type (WT) littermates were randomly chosen to receive daily oral administration of GDC-0941 or a control vehicle. Treated mice exhibited dramatic corrections of leukocytosis and anemia as well as decrease in splenomegaly. Flow cytometry of bone marrow and peripheral populations also imply that GDC-0941 treatment corrects the aberrant proliferation, amends differentiation of bone marrow progenitors, and revives ineffective erythropoiesis found in KrasG12D mice. Treatment also resulted in markedly improved survival of KrasG12D mice; virtually all KrasG12Dmice in the treatment arm outlived their control counterparts. Our data suggest PI3K inhibition may play a role in suppressing hematologic dysfunction in JMML and CMML patients. Potential crosstalk between PI3K and MEK signaling further suggest that combinatorial activities of PI3K and MEK inhibition should be investigated. Disclosures: Friedman: Genentech, Inc.: Employment. Sampath:Genentech, Inc.: Employment.