Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy

Abstract

Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, the dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.

Keywords: Cancer therapy; DNA damage repair; Deregulated of cell death; Drug resistance; Dual-target small molecule; Enhanced drug efflux; Epigenetic alteration; Therapeutic strategy.