Rare cell variability and drug-induced reprgramming: A mode of cancer drug Rx resistance

A major problem in treating a cancer, after it has developed, is that tumor cells (just like bacteria) often exhibit a high rate of mutation –– which serves as a means of survival. Thus, a new cancer drug is given, the cancer cells “sense” this new signal and try hard to develop one or more mutant cells able to survive, in the face of this new cancer drug (chemotherapeutic agent). Melanoma –– which often results from a BRAF gene mutation leading to valine-to-glutamic acid change at residue 600 (V600E) in the BRAF protein –– is a paradigmatic example of resistance to cancer therapy. The drug vemurafenib, which inhibits the BRAF mutant protein, eradicates almost all tumor cells, but a small subset of cancer cells develop drug resistance.

To understand resistance at the single-cell level, authors [see attached article] turned to patient-derived melanoma cells in culture. Cells, isolated from two patients, proliferated readily when grown under normal conditions. A fractional killing dose of vemurafenib (1 μM) stopped the growth of most cells, but sporadic proliferative colonies of resistant cells formed; these surviving cells’ transcriptomes resembled that of drug-resistant cells in patients. Long-term time-lapse imaging –– that captures the onset of resistance –– revealed that drug-resistant colonies can arise from single cells proliferating normally before exposure to the new drug, indicating that these cells are not in a dormant ‘persistent’ state (waiting for a signal to start growing).

Authors [attached] show that human melanoma cells can display profound transcriptional variability at the single-cell level that predicts which cells will ultimately resist drug treatment. This variability involves infrequent, semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. Addition of drug then induces epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably-resistant state. This reprogramming begins with a loss of SOX10-mediated differentiation, followed by activation of new signalling pathways, partially mediated by the activity of transcription factors JUN and/or AP1 and TEAD.

These data reveal the multi-stage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics in single cells. Authors find that other cell types also exhibit sporadic expression of many of these same marker genes –– suggesting the existence of a general program (i.e. “armed and ready to fire”) in which expression is displayed in “rare subpopulations of cells”.

Nature 15 June 2o17; 546: 431–435

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