Editors' ChoiceCancer therapy

Timing matters in combination therapy

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Science Signaling  10 Mar 2020:
Vol. 13, Issue 622, eabb5803
DOI: 10.1126/scisignal.abb5803

Subsequent, not concurrent, treatment with CDK4/6 inhibitors improves the efficacy of chemotherapy.

A hallmark of cancer is a rapid, dysregulated cell cycle. The cyclin-dependent kinases CDK4 and CDK6—often referred to as CDK4/6 due to their redundant functions— promote cell cycle progression and are, therefore, attractive therapeutic targets. Several CDK4/6 inhibitors are currently used in combination with hormone therapy to treat some forms of metastatic breast cancer, and they are being investigated in combination with other treatments in other malignancies. Chemotherapy is the standard treatment for many cancers, including pancreatic ductal carcinoma (PDAC); however, so far, these inhibitors have not been shown to enhance chemotherapeutic efficacy. Salvador-Barbero et al. discovered that changing the timing of this combination strategy may be the key to making it successful. Using PDAC cell lines, patient-derived xenografts, and genetically engineered mice to express mutations frequently observed in PDAC, the authors found that first administering taxane-based chemotherapy or other DNA-damaging agents and then administering CDK4/6 inhibitors slowed tumor growth, delayed cell cycle recovery, and suppressed polyploidy. Transcriptomics, gene ontology analysis, and DNA damage–repair assays together indicated that sequentially treated tumors had durable impairments in homologous recombination (HR) and recovery from chemotherapy-induced chromosomal damage. Notably, CDK4/6 inhibitors also sensitized cells to PARP inhibitors, which exploit HR deficiencies. These findings indicate not only that sequential—not simultaneous—combination of CDK4/6 inhibitors with chemotherapy may be effective but also that these drugs might broaden the use of PARP inhibitors for patients beyond those with HR-deficient tumors.

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