The global cancer burden remains significant, with 10 million diagnoses and 6 million deaths annually. In response, academia and industry are advancing sophisticated therapies, including antibody-drug conjugates (ADCs). These consist of an antibody for tumor selectivity and a cytotoxic drug aimed at killing cancer cells. Most ADCs in clinical trials target the cytoskeleton, but microtubule-targeting agents often lack efficacy, prompting research into drugs with alternative mechanisms. Notable examples include Mylotarg and Besponsa, both approved ADCs with DNA-damaging agents, while SYD985, which uses the DNA-alkylating agent duocarmycin, is currently in promising phase III trials. Despite their potential, ADCs still require improvements in safety and efficacy. Combination therapy may enhance ADC effectiveness, reduce side effects, and slow resistance development, as single-agent therapies are rarely curative. This work focuses on discovering synergistic drug combinations to boost the efficacy of duocarmycin-based ADCs like SYD985.
