Scratching the combinatorial drug landscape surface

Combinations of drugs are a mainstay of most cytotoxic chemotherapeutic regimens and have resulted in dramatic improvements in survival in selected cancers over the past half century. For example, modification of treatment protocols for childhood acute lymphoblastic leukemia have led to incremental but steady improvements in long-term overall survival to nearly 90% using combinations of upwards of six drugs. For most cancers, however, including pre-BRAF-inhibitor-era melanoma, combinations of existing cytotoxic agents have not been nearly so successful, resulting mainly in increases in toxicities without added survival benefit. While results with genotype-directed small molecules as single agents can be dramatic, such as 60-80% response rates in ALK-translocated NSCLC or BRAF mutant melanoma, few patients demonstrate complete responses and most experience relapses in less than a year. Because multiple signaling pathways can induce both primary and acquired resistance, the field is now focused on identifying combinations of these less toxic targeted drugs. © 2013 John Wiley & Sons A/S.