Toward Minimal Residual Disease-Directed Therapy in Melanoma

Publication date: Available online 12 July 2018Source: CellAuthor(s): Florian Rambow, Aljosja Rogiers, Oskar Marin-Bejar, Sara Aibar, Julia Femel, Michael Dewaele, Panagiotis Karras, Daniel Brown, Young Hwan Chang, Maria Debiec-Rychter, Carmen Adriaens, Enrico Radaelli, Pascal Wolter, Oliver Bechter, Reinhard Dummer, Mitchell Levesque, Adriano Piris, Dennie T. Frederick, Genevieve Boland, Keith T. FlahertySummaryMany 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 resi...

Source: Cell - July 12, 2018 Category: Cytology Source Type: research