Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.
X
Mission Bio Blog and Podcast go live! Get the latest news and trends on single-cell multi-omics. Subscribe
X
publication

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


Marin-Bejar, O. et al.
Cancer Cell (2021)
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.



Authors

Marin-Bejar, O., Rogiers, A., Dewaele, M., Femel, J., Karras, P., Pozniak, J., Bervoets, G., Raemdonck, N.V., Pedri, D., Swings, T., Demeulemeester, J., Borght, S.V., Lehnert, S., Bosisio, F., van den Oord, J.J., Bempt, I.V., Lambrechts, D., Voet, T., Bechter, O., Rizos, H., Levesque, M., Leucci, E., Lund, A.W., Rambow, F., Marine, J.C.



VIEW

publication
Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias
Thijssen, R.
Blood (2021)
publication
Personalized single-cell proteogenomics to distinguish acute myeloid leukemia from nonmalignant clonal hematopoiesis
Dillon, L.W.
Blood Cancer Discovery (2021)
publication
PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism
Ren, A.A.
Nature (2021)
publication
Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
Wang, F.
Nature Communications (2021)