Oncotarget
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The mitotic checkpoint protein CHFR has emerged as a major mediator of taxane resistance in cancer. Here we show that CHFR's PAR-binding zinc finger domain (PBZ) mediates a protein interaction with poly-ADP ribosylated PARP1 leading to stabilization of CHFR. Disruption of the CHFR-PARP1 interaction through either PARP1 shRNA-mediated knockdown or overexpression of a PBZ domain peptide induces loss of CHFR protein expression. ⋯ In mouse xenografts, i.p. administration of 'A3' led to a significant reduction in nuclear CHFR protein expression with a maximal effect 4 hours after administration, confirming relevant pharmacodynamics following the peak of 'A3' plasma concentration in vivo. Furthermore, combination of A3 and taxane led to significant reduction of implanted tumor size without increase in hematological, hepatic or renal toxicity. These findings provide a proof-of-principle that small molecule inhibition of CHFR PBZ domain interaction is a novel potential therapeutic approach to increase the efficacy of taxane-based chemotherapy in cancer.
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Mutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20-25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear. ⋯ KRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy.
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Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. ⋯ Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo. We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.