Yazarlar : Weisberg E, Nonami A, Chen Z et al

Yayın : Leukemia

Yayın Yılı : 2014

Pubmed Linki : http://www.docguide.com/identification-wee1-novel-therapeutic-target-mutant-ras-driven-acute-leukemia-and-other-malignancies?tsid=5

Konu : Lösemi

Literatür İçeriği :  Direct targeting of RAS, which is frequently mutated, has proven to be challenging, and inhibition of individual downstream RAS mediators has resulted in limited clinical efficacy. We designed a chemical screen to identify compounds capable of potentiating mTOR inhibition in mutant RAS-positive leukemia, and identified a Wee1 inhibitor. Synergy was observed in both mutant NRAS- and mutant KRAS-positive acute myelogenous leukemia (AML) cell lines and primary patient samples. The observed synergy enhanced dephosphorylation of AKT, 4E-BP1 and S6K, and correlated with increased apoptosis. The specificity of Wee1 as the target of MK-1775 was validated by Wee1 knockdown (KD), as well as partial reversal of drug combination-induced apoptosis by a CDK1 inhibitor. Importantly, we also extended our findings to other mutant RAS-expressing malignancies, including mutant NRAS-positive melanoma, and mutant KRAS-positive colorectal cancer, pancreatic cancer, and lung cancer. We observed favorable responses with combined Wee1/mTOR inhibition in human cancer cell lines from multiple malignancies, and inhibition of tumor growth in in vivo models of mutant KRAS lung cancer and leukemia. The present study introduces for the first time Wee1 inhibition combined with mTOR inhibition as a novel therapeutic strategy to the selective treatment of mutant RAS-positive leukemia and other mutant RAS-expressing malignancies.Leukemia accepted article preview online, 05 May 2014; doi:10.1038/leu.2014.149.

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