Spatial intra-tumour heterogeneity in acquired resistance to targeted therapy complicates the use of PDX models for co-clinical cancer studies

Targeted therapy in the treatment of cancer has produced great clinical successes. However, with these came the challenge of acquired resistance. Melanoma, a cancer that carries one of the highest mutational burdens, displays great complexity in mutational acquired resistance with a notable degree of inter-tumoural heterogeneity. In this issue of EMBO Molecular Medicine, Kemper et al (2015) describe the identification of multiple, partly novel resistance mechanisms present in one patient and within a single metastasis, where one mutation could be traced back to a pre-treatment lesion. Importantly, the observed intra-tumoural “spatial” heterogeneity can impact on the interpretability of patient-derived xenografts, and this might have implications particularly for co-clinical treatment studies.