Editors' ChoiceCancer

Improving cancer combination therapy by timing drug administration

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Science Translational Medicine  15 Apr 2020:
Vol. 12, Issue 539, eabb5671
DOI: 10.1126/scitranslmed.abb5671

Abstract

Sequential treatment provides therapeutic benefit in pancreatic cancer models.

Drug combinations of targeted agents with chemotherapies have been proposed to enhance therapeutic response in cancer. Cell cycle deregulation is common in pancreatic ductal adenocarcinoma, and cyclin-dependent kinase (CDK) 4/6 inhibitors provide a promising targeted therapeutic strategy. However, previous studies have shown that the growth-inhibiting effects of CDK4/6 inhibitors protect proliferating tumor cells from the cytotoxic effects of concurrent chemotherapy. Hence, a comprehensive understanding of how cancer cells respond to each drug in the regimen is necessary to design optimal combination therapies.

Salvador-Barbero et al. used pancreatic ductal adenocarcinoma models to investigate the effects of timing CDK4/6 inhibition on the efficacy of antimitotic and DNA-damaging chemotherapy. Pretreatment with CDK4/6 inhibitors hindered the antiproliferative effects of taxane-based chemotherapy in vitro, while CDK4/6 inhibition following treatment with chemotherapy resulted in reduction of cell growth. The benefit of this sequential combination treatment strategy compared with either single agent was also demonstrated in both immune-deficient and immune-competent mouse models. Cancer cells underwent cell division following recovery from single-agent treatment with taxanes; however, this recovery was blocked by post-chemotherapy treatment with CDK4/6 inhibitors. Transcriptomic analysis uncovered that the drug combination down-regulated DNA repair–related genes; this was also demonstrated using a functional assay for homologous recombination efficiency. Lastly, the suppressive activity of CDK4/6 inhibitors on DNA repair processes was also shown for DNA-damaging chemotherapy agents such as gemcitabine, platinums, and irinotecan.

The results by Salvador-Barbero et al. on sequential drug combinations, in which the second drug exploits the vulnerability induced by the first drug, provide an important paradigm of rational combination therapy design. Future studies are needed to investigate the potential of modulating immune system function by including immune-targeted drugs that could result in long-lasting treatment effects. This is a critical issue because tumors will eventually relapse following growth inhibition by the CDK4/6 inhibitor and taxanes. Clinical translation will also benefit greatly from the discovery of biomarkers that identify what tumor characteristics associate with maximum benefit from this combination therapy.

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