Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma
| Autor: | Oskar Marín-Béjar, Toon Swings, Jean-Christophe Marine, Florian Rambow, Amanda W. Lund, Aljosja Rogiers, Francesca Maria Bosisio, Michael Dewaele, Joanna Pozniak, Dennis Pedri, Isabelle Vanden Bempt, Eleonora Leucci, Panagiotis Karras, Helen Rizos, Mitchell P. Levesque, Thierry Voet, Stefan Lehnert, Julia Femel, Sara Vander Borght, Diether Lambrechts, Joost van den Oord, Oliver Bechter, Jonas Demeulemeester, Greet Bervoets, Nina Van Raemdonck |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Mice SCID 0302 clinical medicine Oximes Melanoma education.field_of_study Imidazoles Gene Expression Regulation Neoplastic medicine.anatomical_structure Oncology Neural Crest FAK signaling 030220 oncology & carcinogenesis Neoplastic Stem Cells Female Stem cell Proto-Oncogene Proteins B-raf therapy resistance Pyridones Population Antineoplastic Agents Pyrimidinones Biology single-cell sequencing Focal adhesion 03 medical and health sciences cutaneous melanoma Cell Line Tumor medicine Animals Humans Glial Cell Line-Derived Neurotrophic Factor education Protein kinase A Protein kinase B Protein Kinase Inhibitors patient-derived tumor xenografts Mitogen-Activated Protein Kinase Kinases neural crest stem cells medicine.disease Minimal residual disease Xenograft Model Antitumor Assays 030104 developmental biology Drug Resistance Neoplasm Focal Adhesion Kinase 1 Cancer research minimal residual disease Neoplasm Recurrence Local nongenetic reprogramming |
| Zdroj: | Cancer Cell |
| Popis: | 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. ispartof: CANCER CELL vol:39 issue:8 pages:1135-+ ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|