Resistance
Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma
Abstract
Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to MAPK therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a GDNF-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to ERK inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.
Single-cell RNA sequencing of about 20k melanoma cells before treatment (T0) and at MRD showing emergence of the NCSC state (based on the AUCell score) in the MEL006, but not MEL015, PDX model.
Data Availability
Targeted DNA sequencing data (TruSight, Illumina) of the different PDX models were submitted to the European Genome Archive (EGAS00001005314) as well as whole-exome sequencing and SNP array data of MEL006 and scRNAseq of MEL006 and MEL015.