Inhibiting resistance acquisition by epigenetically altering tumour heterogeneity.

Lung cancer cell phenotypes are notoriously heterogeneous and highly plastic. In the face of therapy, subpopulations often show intrinsic resistance or undergo phenotype switching to acquire resistance. This project’s cardinal hypothesis is that this heterogeneity and plasticity are epigenetically regulated, and that they control the acquisition of drug resistance. To test this hypothesis, we will combine CRISPR and epigenetic inhibitor screens with single cell RNA-seq to measure how blocking epigenetic enzyme activity affects cellular heterogeneity and therapy response. The role of epigenetic drivers of heterogeneity in therapy response will be validated by assessing how they affect drug tolerance of cancer cells, and whether reducing heterogeneity curbs resistance acquisition. Signatures of heterogeneity can be applied to ongoing scRNAseq studies of cancer patients, to understand what aspects of heterogeneity contribute to clinical outcome. We ultimately aim to improve patient outcome by understanding tumour heterogeneity.