Gall Mas, L.; Kleinmanns, K.; Pirttikoski, A.; Santarelli, M.; Stangeland, G.; Dai, J.; Marin Falco, M.; Fontaneda-Arenas, D.; Doerr, C.; Hautaniemi, S.; Hynninen, J.; McCormac, E.; Wennerberg, K.; Bjorge, L.; Vähärautio, A.; Schwikowski, B.

In high-grade serous carcinoma (HGSC), extensive intra-tumoral heterogeneity hinders complete eradication and remains a major obstacle to developing combination therapies capable of eliminating subpopulations resistant to standard-of-care treatment. Using single-cell RNA sequencing of 72 samples from 54 HGSC patients spanning treatment-naive, post-neoadjuvant chemotherapy and relapse stages, we established a carboplatin-anchored framework that identifies transcriptional signatures of intrinsic (pre-existing) and adaptive (therapy-induced) resistance in individual tumors and prioritizes mechanistically matched drugs to potentiate carboplatin efficacy. Candidate compounds were ranked by integrating orthogonal resources--viability (GDSC, PRISM) and perturbational transcriptomics (L1000, Perturb-seq)--to reduce context bias. Among 64 candidates, three carboplatin adjuvants enhanced long-term efficacy in patient-derived organoids (PDOs), and pevonedistat further significantly reduced tumor burden in orthotopic xenografts. This tiered validation pipeline--from short-term and long-term PDOs and in vivo orthoptic xenografts--establishes a translational framework linking single cell resistance programs to actionable, tumor-specific, carboplatin-anchored combinations for HGSC.