Therapeutic options in cancer have improved dramatically in recently years, but unfortunately, resistance remains a major clinical hurdle. While numerous genetic and non-genetic factors are emerging as important mediators, pharmacological factors determining both intrinsic and acquired resistance remain under-explored.
We are interested in whether differential drug accumulation at the cellular level could be a factor determining inter-patient heterogeneity in drug response. Similarly, we are exploring how drug accumula)on varies within a patient’s tumour, and whether pockets of low drug accumula)on can give rise to drug resistance.
Here, I will discuss our use of multi-modal tissue imaging to explore this idea in in ovarian High Grade Serous Carcinoma patient-derived explants. We examined the distribution of three clinically used PARP inhibitors using mass spectrometry imaging, and used spatial transcriptomics to investigate both the molecular factors driving differential accumulation and its consequences for drug response. We have observed substantial heterogeneity in drug distribution both within and between tumours, and both this heterogeneity its implications for drug response are recapitulated at the single cell level in cell lines, enabling a deeper exploration of underlying mechanisms.