Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, BRAF INHIBITOR RESISTANCE, STEM-CELLS, THERAPY, DIFFERENTIATION, MECHANISMS, DYNAMICS, LEUKEMIA, REVEALS, DISEASE, STATE, FAK signaling, cutaneous melanoma, minimal residual disease, neural crest stem cells, nongenetic reprogramming, patient-derived tumor xenografts, single-cell sequencing, therapy resistance, Animals, Antineoplastic Agents, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Focal Adhesion Kinase 1, Gene Expression Regulation, Neoplastic, Glial Cell Line-Derived Neurotrophic Factor, Humans, Imidazoles, Melanoma, Mice, SCID, Mitogen-Activated Protein Kinase Kinases, Neoplasm Recurrence, Local, Neoplastic Stem Cells, Neural Crest, Oximes, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Xenograft Model Antitumor Assays, Mice, C16/19/006#55215869, C14/18/092#54689607, 12J6921N#55744105, 1S79619N|1S79621N#54761390, 1109 Neurosciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology, 3211 Oncology and carcinogenesis

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 mitogen-activated protein kinase 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 glial cell line-derived neurotrophic factor-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 extracellular signal-regulated kinase 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.