Oncotarget

Research Papers:

Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia

Stacey J. Baker _, Stephen C. Cosenza, M.V. Ramana Reddy and E. Premkumar Reddy

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Oncotarget. 2019; 10:1932-1942. https://doi.org/10.18632/oncotarget.26735

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Abstract

Stacey J. Baker1, Stephen C. Cosenza1, M.V. Ramana Reddy1, and E. Premkumar Reddy1,2

1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

2Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Correspondence to:

Stacey J. Baker, email: stacey.baker@mssm.edu

E. Premkumar Reddy, email: ep.reddy@mssm.edu

Keywords: rigosertib; RAS; hematopoiesis; myeloproliferative disorder

Received: January 04, 2019     Accepted: February 08, 2019     Published: March 08, 2019

ABSTRACT

Aberrant signaling triggered by oncogenic or hyperactive RAS proteins contributes to the malignant phenotypes in a significant percentage of myeloid malignancies. Of these, juvenile myelomonocytic leukemia (JMML), an aggressive childhood cancer, is largely driven by mutations in RAS genes and those that encode regulators of these proteins. The Mx1-cre kras+/G12D mouse model mirrors several key features of this disease and has been used extensively to determine the utility and mechanism of small molecule therapeutics in the context of RAS-driven myeloproliferative disorders. Treatment of disease-bearing KRASG12D mice with rigosertib (RGS), a small molecule RAS mimetic that is in phase II and III clinical trials for MDS and AML, decreased the severity of leukocytosis and splenomegaly and extended their survival. RGS also increased the frequency of HSCs and rebalanced the ratios of myeloid progenitors. Further analysis of KRASG12D HSPCs in vitro revealed that RGS suppressed hyperproliferation in response to GM-CSF and inhibited the phosphorylation of key RAS effectors. Together, these data suggest that RGS might be of clinical benefit in RAS-driven myeloid disorders.


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