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

Marin-Bejar O, Rogiers A, Dewaele M, Femel J, Karras P, Pozniak J, Bervoets G, Van Raemdonck N, Pedri D, Swings T, Demeulemeester J, Borght SV, Lehnert S, Bosisio F, van den Oord JJ, Bempt IV, Lambrechts D, Voet T, Bechter O, Rizos H, Levesque MP, Leucci E, Lund AW, Rambow F, Marine JC.
Cancer Cell Aug 2021

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.



Solid Tumor

Institution Type


Indication / Modality


Goal of Study

Therapeutic Resistance, Tumor Profiling, MRD

Key Genes


PAD Project


Analytes Assessed

SNV, InDels

Sample Storage

Fresh Frozen

Sample Prep

Nuclei Prep

Sample Type

Patient Derived Xenograft, Patient Material

Tissue / Organ



Mouse, Human

Panel Used

Tumor Hotspot Panel

Proof Point Demonstrated