ResMap: A community resource for systematic mapping of therapy-persistent residual cancer cell dependencies across contexts.

Relapse following targeted therapy remains a central challenge in oncogene-driven cancers. Drug-tolerant persister cells that survive initial treatment without genetic resistance seed relapse, yet despite over a decade of research, no persister-directed therapy has reached clinical approval. To bridge this gap, we developed ResMap, a community resource providing both a standardized experimental framework and quantitative dataset for systematic comparison of persister vulnerabilities across cancer contexts. Using this platform, we evaluated 94 compounds targeting 57 literature-derived candidates in two EGFRmut and two KRASG12C lung cancer models under normoxic and hypoxic conditions. Initial screening identified 12 targets with conserved anti-persister activity across genotypes and oxygen environments; follow-up validation reproduced 9 of these targets and revealed variable degrees of persister specificity relative to general cytotoxicity. We also identified context-specific vulnerabilities, including KRAS-relevant combination targets, several of which have since been independently reported and/or advanced to clinical testing. Integration of human cancer cell line essentiality data and adult mouse loss-of-function phenotypes provided a complementary tolerability layer to refine prioritization. ResMap establishes a foundation for coordinated community efforts to accelerate rational persister-directed combination strategies toward the clinic.