Editors' ChoiceCancer

How to make a cocktail

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Science Translational Medicine  05 Oct 2016:
Vol. 8, Issue 359, pp. 359ec158
DOI: 10.1126/scitranslmed.aai8745

Although targeted therapies have significantly improved outcomes for patients across a number of cancer types, primary and acquired resistance remain considerable challenges. To inhibit resistance, the development of combination drug approaches cotargeting bypass and crosstalk signaling pathways may be more effective than targeted monotherapies. However, identifying the most effective drug cocktail to take into the clinic is often challenging due to tumor heterogeneity, complex biology, concerns for additive toxicity, and ineffective preclinical readouts.

In a recent study, Horn et al. systematically assessed the efficacy of drug combinations across 23 colorectal cancer (CRC) cell lines. Using a library of drugs predicted to target CRC tumorigenesis and progression, pairwise and triple combinations at multiple dose levels were evaluated for effects on cellular viability and apoptosis by high-throughput imaging. To enhance cytotoxicity, additional drugs targeting downstream processes such as apoptosis and cell cycle progression were added to select drug combinations, resulting in high-order combinations. Overall, triple combinations proved more effective at inducing cell death than pairwise synergies. Novel drug synergies were identified, including agents targeting the RAS/MAPK and PI3K/AKT pathways combined with agents targeting CDK4/6, MDM2, or BCL2-family proteins. Combinations consisting of up to six drugs were also tested in resistant cell lines. CRC responses were influenced not only by the genetic mutations within the tumor cell lines but also by the expression of anti-apoptotic proteins, the drugs’ mechanisms of action, and the number of drugs used.

Genotype-driven early targeting of adaptive and acquired drug resistance through multidrug therapy is a strategy that has been adopted as standard and proven remarkably effective for other diseases, such as human immunodeficiency virus (HIV), but has been challenging to broadly implement in cancer. This study highlights the great potential of using higher-order drug screening to identify novel drug combinations in cancer. This systematic approach along with its growing knowledge base will fuel preclinical work to evaluate mechanisms of synergy and inform ongoing and future clinical trials.

T. Horn et al., High order drug combinations are required to effectively kill colorectal cancer cells. Cancer Res. 10.1158/0008-5472.CAN-15-3425 (2016). [Abstract]

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