Evolutionary predictability of genetic versus non genetic resistance to anticancer drugs in melanoma

Study ID Alternative Stable ID Type
EGAS00001005314 Other

Study Description

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 ... (Show More)

Study Datasets 2 datasets.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
WES: (7 samples, BAM files), scRNA-Seq (4 samples, BAM files), TruSight (56 samples, BAM or FASTQ files)
Illumina HumanCytoSNP-12v2.1 BeadChip
BeadChip 7

Who archives the data?

There are no publications available