A MEK Inhibitor Abrogates Myeloproliferative Disease in Kras Mutant Mice

Abstract

Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are aggressive myeloproliferative neoplasms that are incurable with conventional chemotherapy. Mutations that deregulate Ras signaling play a central pathogenic role in both disorders, and Mx1-Cre, KrasLSL-G12D mice that express the Kras oncogene develop a fatal disease that closely mimics these two leukemias in humans. Activated Ras controls multiple downstream effectors, but the specific pathways that mediate the leukemogenic effects of hyperactive Ras are unknown. We used PD0325901, a highly selective pharmacological inhibitor of mitogen-activated protein kinase kinase (MEK), a downstream component of the Ras signaling network, to address how deregulated Raf/MEK/ERK signaling drives neoplasm formation in Mx1-Cre, KrasLSL-G12D mice. PD0325901 treatment induced a rapid and sustained reduction in leukocyte counts, enhanced erythropoiesis, prolonged mouse survival, and corrected the aberrant proliferation and differentiation of bone marrow progenitor cells. These responses were due to direct effects of PD0325901 on Kras mutant cells rather than to stimulation of normal hematopoietic cell proliferation. Consistent with the in vivo response, inhibition of MEK reversed the cytokine hypersensitivity characteristic of KrasG12D hematopoietic progenitor cells in vitro. Our data demonstrate that deregulated Raf/MEK/ERK signaling is integral to the growth of Kras-mediated myeloproliferative neoplasias, and further suggest that MEK inhibition could be a useful way to ameliorate functional hematologic abnormalities in patients with CMML and JMML.

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors

“…This was unexpected, as the MEK inhibitor from which PD0325901 was derived failed to show efficacy in a GEM model of Nf1 JMML (53). Recently, PD0325901 was found to be effective in reversing myeloproliferative disease in an activated KRas mouse model (54) and in Nf1-driven JMML (33), likely due to the more persistent inhibition of MEK by PD0325901, a second-generation MEK inhibitor modified to improve efficacy for clinical cancer trials (55). Collectively, these studies suggest that Raf/MEK/ERK is a critical pathway in NF1.…”

RAS diseases in children

“…Selective inhibition of MEK abrogated the myeloproliferative disease in Nf-1 and Kras mutant mice 103,104 suggesting that MEK inhibitors might ameliorate hematologic abnormalities in JMML. Although therapeutic windows for pan inhibitors of the MAPK pathway may be limited,1 early clinical studies in JMML are needed to gain more insight into the specific signaling network of this rare disease.…”

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

“…30,55,56 Previous work has demonstrated that MEK inhibition can attenuate myeloid neoplasia but is insufficient to cure this disease in either mouse models or human patients. 23,[56][57][58] Kras G12D myeloid cells remain hypersensitive to cytokines (according to colonyforming assays) despite MEK inhibition. 23 Jak inhibition abrogates GM-CSF-dependent ERK phosphorylation in Kras G12D myeloid cells.…”

“…23,[56][57][58] Kras G12D myeloid cells remain hypersensitive to cytokines (according to colonyforming assays) despite MEK inhibition. 23 Jak inhibition abrogates GM-CSF-dependent ERK phosphorylation in Kras G12D myeloid cells. 59 These results indicate that other pathways contribute to disease in leukemias with hyperactive RAS signaling.…”

“…In an activated Kras model of MPN, Mek inhibition abrogated the disease. 23 In mouse models of Nf1-deficient or Kras-mutant MPN, Mek inhibition enhanced erythropoiesis and reduced spleen size, but failed to eradicate Nf1-deficient or Krasmutant cells. 23,24 These studies support a central role of aberrant Raf/MEK/ERK signaling in the abnormal growth of JMML cells.…”