Identification and characterisation of drug-tolerant state(s) induced by MAPK-inhibition

A major obstacle to successful targeted therapy is the acquisition by cancer cells of a plethora of resistance-conferring genetic alterations that greatly attenuate or suppress the effect of the drug(s). Different mutational events can be selected in distinct drug-resistant clones from the same patient and even co-occur within the same lesion, thus creating genetic intra-tumor heterogeneity. These findings have highlighted the need to improve effectiveness of treatment before mutational acquired resistance prevails. Recent cell culture findings indicate that acquired mutational resistance to cancer drugs may follow a transient and reversible “drug-tolerant” phase in which a small subpopulation of drug-tolerant cells remain viable whereas the vast majority of the cell population is rapidly killed. Understanding the molecular mechanisms underlying the selection of drug-tolerant subpopulations is essential for the design of rational combination therapies that prevent the development of resistance. Identification and characterization of the drug-tolerant subpopulation may allow their selective ablation before more permanent/stable resistance mechanisms are established. We established a patient-derived xenograft model as an appropriate in vivo model of tolerance, using MAPK-targeted therapy of BRAF-mutant melanoma as a paradigm. Herein, we propose to study drug tolerance dynamics and heterogeneity in vivo by leveraging the power of single-cell profiling techniques.