Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Transcriptional dysregulation by transcription factors (TF) is central to cancer development.
• The global impact of TF activity on anticancer drug sensitivity remains largely unexplored.

Purpose of the Study:

• To investigate the relationship between TF activity and drug sensitivity across a large cohort of cancer cell lines and tumors.
• To identify TFs that modulate responses to anticancer agents.
• To assess the utility of TF activity in refining personalized cancer treatment strategies.

Main Methods:

• Inferred TF activity from RNA-seq gene expression data in 1,056 cancer cell lines and 9,250 primary tumors.
• Validated TF activity predictions using shRNA essentiality and gene deletion data.
• Analyzed cell line responses to 265 compounds to identify drug-TF interactions.

Main Results:

• Identified numerous TFs whose activity significantly interacts with anticancer drug responses.
• Demonstrated that integrating TF activity with existing pharmacogenomic markers enhances cell line stratification for drug treatment.
• TF activity predictions were supported by independent biological data, recapitulating cancer-specific dysregulation mechanisms.

Conclusions:

• Systematic analysis of TF activity provides a foundation for understanding cancer drug sensitivity.
• This research offers a publicly accessible resource (dorothea.opentargets.io) to guide the development of personalized cancer therapies.
• TF activity is a valuable biomarker for predicting and potentially improving patient response to cancer treatments.