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Beeharry N , Banina E , Hittle J , Skobeleva N , Khazak V , Deacon S , Andrake M , Egleston BL , Peterson JR , Astsaturov I , Yen TJ
Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints
Cell Cycle. 2014 Jul;13(14) :2172-91
PMID: 24955955    PMCID: PMC4111673    URL: https://www.ncbi.nlm.nih.gov/pubmed/24955955
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Abstract
Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as "authentic" bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents' gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient's tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers.
Notes
Beeharry, Neil Banina, Eugenia Hittle, James Skobeleva, Natalia Khazak, Vladimir Deacon, Sean Andrake, Mark Egleston, Brian L Peterson, Jeffrey R Astsaturov, Igor Yen, Timothy J eng R21 CA164205/CA/NCI NIH HHS/ CA06927/CA/NCI NIH HHS/ CA169706/CA/NCI NIH HHS/ R01 CA188430/CA/NCI NIH HHS/ K22 CA160725/CA/NCI NIH HHS/ R01 GM083025/GM/NIGMS NIH HHS/ R21 CA169706/CA/NCI NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Cell Cycle. 2014;13(14):2172-91. doi: 10.4161/cc.29214. Epub 2014 Jun 23.