Duchemin, Q.; Trejo Banos, D.; Bertolini, A.; Ferreira, P. F.; Schill, R.; Lienhard, M.; Wegmann, R.; Tumor Profiler Consortium, ; Snijder, B.; Stekhoven, D.; Beerenwinkel, N.; Singer, F.; Obozinski, G.; Kuipers, J.

Tumour heterogeneity presents a major challenge for precision oncology, as genetically and phenotypically distinct tumour clones may respond differently to therapy. To address this, we introduce scClone2DR, a probabilistic multi-modal framework that predicts drug responses at the level of individual tumour clones by integrating single-cell DNA and RNA sequencing with ex-vivo drug-screening data. In simulations, scClone2DR substantially outperforms alternatives in recovering true drug effects and clonal sensitivities. Applied to 60 melanoma and 21 acute myeloid leukaemia patient samples, the method identifies heterogeneous clonal responses, yields biologically meaningful feature rankings, highlights clones that may be resistant to treatment, and improves the prediction of clinical outcomes compared to models ignoring clonal structure. These results demonstrate that modelling tumour evolution and clonal diversity is crucial for accurate drug-response prediction and provides a foundation for more effective, clone-aware precision oncology.