Screening for regulators of gene expression variability that drive drug resistance in melanoma
Eduardo A. Torre, Sydney Shaffer, Benjamin Emmert, Eri Arai, Junwei Shi, Arjun Raj
University of Pennsylvania.
In patients with melanoma, targeted therapeutics such as Vemurafenib initially lead to a strong response, but in the majority of cases drug resistance eventually arises. The origin of this resistance can be both genetic and non-genetic. In previous work, we have shown that clonal melanoma cells, as wells as other types of tumor cells, display considerable transcriptional variability at the single cells level. This variability involves infrequent, semi-coordinated transcription of several genes associated with resistance in a small percentage of cells. This phenotypic state ultimately predicts which cells survive drug exposure. Here, I further explore the mechanisms driving this profound transcriptional variability and the clinical consequences of induced changes to this phenotypic state through a small molecule screen and pooled CRISPR screen.