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  • Many investigators participated in the studies on

    2019-07-30

    Many investigators participated in the studies on the regulation of the ARCA and experiments indicated that the process was conserved across many eukaryotic species including humans [127]. Because cancer cells exhibit dysregulated cell division along with the presence of abnormal chromosome numbers (aneuploidy) [131], it was natural to focus on cell cycle inhibitors as potential anticancer agents [132]. Among the first studies addressing the potential of CDK antagonists as anticancer agents was that by Kaur et al. in 1992 who investigated the effects of alvocidib (flavopiridol) on several breast and lung cancer cell lines [133]. It was not until 2015 that palbociclib in combination with letrozole was approved by the FDA as a first-line treatment for HR+/HER2– breast cancer (www.brimr.org/PKI/PKIs.htm). The FDA subsequently approved the combination of palbociclib and fulvestrant as a second-line therapy in women with disease progression following endocrine therapy. The development of a clinically approved CDK4/6 inhibitors required about two dozen years, which contrasts with the time-line for the development of an ALK antagonist (crizotinib) over four years or EGFR inhibitors (erlotinib and gefitinib) over nine years [54]. As noted in Table 4, abemaciclib, palbociclib, ribociclib, and other CDK antagonists are undergoing clinical trails for a variety of cancers as a single agent or as part of a combination of drugs. One of the main difficulties in cancer therapy is the development of resistance to both targeted and nontargeted drugs. Owing to the recent introduction of CDK inhibitors into the clinic, only lately have there been studies addressing mechanisms of resistance to these agents [134,135]. Preclinical studies suggest that secondary or acquired resistance may be mediated by AKT/PKB and mTOR signaling pathway that remains active in the presence of CDK4/6 inhibitors [136]. Preclinical studies performed by Yang et al. suggest that CDK6 gene amplification and decreased expression of the estrogen and progesterone receptors may contribute to resistance [137]. Moreover, these investigators observed reduced hormone receptor expression in tumor samples taken from patients who had developed resistance to abemaciclib or ribociclib. One strategy for minimizing the development of resistance is the use of combination therapies. The use of palbociclib or ribociclib in combination with exemestane (an aromatase inhibitor) and everolimus (an mTOR inhibitor that is FDA-approved for the treatment of HER2– breast cancer) represents one strategy for mitigating drug resistance by targeting multiple signaling pathways [138]. Devising protocols for minimizing or overcoming resistance to cancer therapies constitutes one of the most important problems faced by biomedical scientists and oncologists who work on anticancer therapies.
    Conflict of interest
    Acknowledgments The colored figures in this paper were evaluated to ensure that their perception was accurately conveyed to colorblind readers [139]. The author thanks Laura M. Roskoski for providing editorial and bibliographic assistance. I also thank Josie Rudnicki and Jasper Martinsek for their aid in preparing the figures and Pasha Brezina and W.S. Sheppard for their help in structural analyses.
    Introduction Although over 20 differently selective inhibitors of cyclin-dependent kinases (CDKs) have been tested in clinical trials, only PD-0332991 (Palbociclib) and SCH-727965 (Dinaciclib), have recently entered phase III clinical trials for the treatment of patient with breast cancer and chronic lymphocytic leukemia, respectively (clinicaltrials.gov). The clinical progress of similar candidate drugs has been delayed or even terminated not only due to undesirable side effects but also because of their unclear or unpredictable mechanisms of action.1, 2, 3, 4 Despite the complexity of selectivity of CDK inhibitors, some suitable diagnoses for experimental treatment have emerged. This applies especially for CDK1, 2, 4 and 9 inhibitors. For example, inhibition of CDK4 has been shown to be of benefit in the treatment of breast cancer characterized by increased expression of oncogenes Erbb2 and Ras. Another study showed that a lack of CDK4 (or its pharmacological inhibition) might be critical in c-Myc-induced skin cancer. Although the mitotic CDK1 seems to be essential for cell division and its deficiency results in embryonic lethality in mice, its inhibition seems to be advantageous in the treatment of human malignancies overexpressing MYC.9, 10 Despite the fact that CDK2 appears to be dispensable for the cell cycle and proliferation,8, 11, 12 another study has indicated that CDK2 activity in melanoma is largely maintained at the transcriptional level by MITF (melanocyte lineage transcription factor) and shows unique regulation correlating with drug sensitivity. Finally, inhibition of transcriptional CDK9 has been established as a promising strategy in the treatment of multiple myeloma or chronic lymphocytic leukemia2, 14, 15 due to their dependence on CDK9-regulated genes with short half-lives involved in the regulation of apoptosis.