Abstract
Most experimental cancer drugs ultimately fail during the course of clinical development, contributing to the high cost of the few that are granted regulatory approval. Moreover, approved drugs often deliver only modest clinical benefit to patients with advanced disease due to the development of resistance. Here, we discuss opportunities we consider promising to overcome drug resistance associated with interactions between signaling pathways and the presence of multiple coexisting cell states within tumors with distinct vulnerabilities. We highlight how understanding drug-resistance mechanisms can enable innovative treatment regimens that deliver longer-lasting benefit to patients.