Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia.
| Autor: | Baker SJ; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Cosenza SC; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Ramana Reddy MV; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Premkumar Reddy E; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Oncotarget [Oncotarget] 2019 Mar 08; Vol. 10 (20), pp. 1932-1942. Date of Electronic Publication: 2019 Mar 08 (Print Publication: 2019). |
| DOI: | 10.18632/oncotarget.26735 |
| Abstrakt: | 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 KRAS G12D 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 KRAS G12D 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. Competing Interests: CONFLICTS OF INTEREST EPR is an equity holder, board member and a paid consultant of Onconova Therapeutics, Inc. MVRR and SCC are stockholders and paid consultants of Onconova Therapeutics Inc. SJB is a paid consultant of Onconova Therapeutics Inc. All authors are named inventors on pending and/or issued patents filed by Temple University. |
| Databáze: | MEDLINE |
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