Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are rare myeloid neoplasms with poor prognoses.
• Aberrant Ras pathway signaling due to mutations in NRAS, KRAS, PTPN11, CBL, and NF1 is a hallmark of CMML and JMML.
• Current treatments for CMML and JMML are largely ineffective, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the therapeutic potential of targeting Ras-regulated effector pathways, specifically the phosphoinositide-3'-OH kinase (PI3K)/Akt cascade, in CMML and JMML.
• To evaluate the efficacy of PI3K and Akt inhibitors in preclinical mouse models of these myeloid malignancies.

Main Methods:

• Utilized Mx1-Cre, Kras(D12) and Mx1-Cre, Nf1(flox/)(-) mouse models that accurately recapitulate key features of CMML and JMML.
• Administered GDC-0941 (a PI3K inhibitor) and MK-2206 (an Akt inhibitor) to evaluate their impact on hematologic parameters and survival.
• Assessed the effects of these inhibitors on both PI3K/Akt and Raf/MEK/ERK signaling pathways in primary hematopoietic cells.

Main Results:

• Treatment with GDC-0941 reduced leukocytosis, anemia, and splenomegaly, extending survival in Kras(D12) mice.
• GDC-0941 treatment affected both PI3K/Akt and Raf/MEK/ERK pathways, suggesting potential off-target effects or complex pathway interactions.
• Administration of the Akt inhibitor MK-2206, without impacting Raf/MEK/ERK signaling, induced significant hematologic improvements in Kras and Nf1 mouse models of myeloproliferative neoplasms.

Conclusions:

• The PI3K/Akt pathway is a critical driver in CMML and JMML pathogenesis.
• Targeting the Akt pathway specifically, independent of Raf/MEK/ERK signaling, offers a promising therapeutic avenue for CMML and JMML.
• These findings support the clinical investigation of PI3K/Akt pathway inhibitors for patients diagnosed with CMML and JMML.