Genetic screening for single-cell variability modulators driving therapy resistance

A genetic screen designed to capture modulators of single-cell state variability identifies a new mode of altering resistance to BRAF inhibition in melanoma that pushes cells toward a more differentiated state. Modulating cellular plasticity may provide a new avenue to overcome drug resistance. Cellular plasticity describes the ability of cells to transition from one set of phenotypes to another. In melanoma, transient fluctuations in the molecular state of tumor cells mark the formation of rare cells primed to survive BRAF inhibition and reprogram into a stably drug-resistant fate. However, the biological processes governing cellular priming remain unknown. We used CRISPR-Cas9 genetic screens to identify genes that affect cell fate decisions by altering cellular plasticity. We found that many factors can independently affect cellular priming and fate decisions. We discovered a new plasticity-based mode of increasing resistance to BRAF inhibition that pushes cells towards a more differentiated state. Manipulating cellular plasticity through inhibition of DOT1L before the addition of the BRAF inhibitor resulted in more therapy resistance than concurrent administration. Our results indicate that modulating cellular plasticity can alter cell fate decisions and may prove useful for treating drug resistance in other cancers.

Automated summary

A genetic screen identified a new mode of altering resistance to BRAF inhibition in melanoma by increasing cellular plasticity and pushing cells towards a more differentiated state. Modulating cellular plasticity may alter cell fate decisions and prove useful for treating drug resistance in other cancers.