Toward Minimal Residual Disease-Directed Therapy in Melanoma.
By F. Rambow, A. Rogiers, O. Marin‐Bejar, S. Aibar, Julia Femel, M. Dewaele, D. Brown, Y. Chang, M. Debiec-Rychter, C. Adriaens and 14 more. Cell, 2018
648 citations recorded by the source corpus.
Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
View Paper: https://www.semanticscholar.org/paper/4b66271e1427f9d4ed086ff1a86fc54d2068e703
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Citations in the corpus
- Dynamic EMT: a multi‐tool for tumor progression (2021, unknown): “In BRAF-mutant melanoma, ZEB1 is sufficient and only partly compensated by TWIST to promote an undifferentiated p75 high neural crest stem cell-like state that is characterized by resistance to MAPK and BRAF inhibitors (Richard et al , 2016; Shaffer et al , 2017; Rambow et al , 2018).”
- Methods and applications for single-cell and spatial multi-omics (2023, background): “Additionally, it will allow the study of how cells within these genetic subclones putatively apply cell plasticity to change their gene expression repertoire and accommodate different phenotypic cancer cell states able to withstand drug treatment and, eventually, acquire resistance 22 .”
- Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity (2020, background): “In malignant melanoma, BRAF- and MEK inhibitor-tolerant cells exhibit multiple transcriptional states [181] and, over the last years, a number of acquired resistance mechanisms were discovered (reviewed in [12,13] and Figure 3).”