A genetic map of the chromatin regulators to drug response in cancer cells

Abstract

Background: Diverse drug vulnerabilities owing to the Chromatin regulators (CRs) genetic interaction across various cancers, but the identification of CRs genetic interaction remains challenging.

Methods: In order to provide a global view of the CRs genetic interaction in cancer cells, we developed a method to identify potential drug response-related CRs genetic interactions for specific cancer types by integrating the screen of CRISPR-Cas9 and pharmacogenomic response datasets.

Results: Totally, 625 drug response-related CRs synthetic lethality (CSL) interactions and 288 CRs synthetic viability (CSV) interactions were detected. Systematically network analysis presented CRs genetic interactions have biological function relationship. Furthermore, we validated CRs genetic interactions induce multiple omics deregulation in The Cancer Genome Atlas. We revealed the colon adenocarcinoma patients (COAD) with mutations of a CRs set (EP300, MSH6, NSD2 and TRRAP) mediate a better survival with low expression of MAP2 and could benefit from taxnes. While the COAD patients carrying at least one of the CSV interactions in Vorinostat CSV module confer a poor prognosis and may be resistant to Vorinostat treatment.

Conclusions: The CRs genetic interaction map provides a rich resource to investigate cancer-associated CRs genetic interaction and proposes a powerful strategy of biomarker discovery to guide the rational use of agents in cancer therapy.

Keywords: Cancer therapy; Chromatin regulators; Drug response; Synthetic lethality; Synthetic viability.