Multi-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer...

Area of Science:

• Oncology
• Systems Biology
• Pharmacology

Background:

• Broad drug resistance is a major challenge in cancer therapy, stemming from complex genetic and molecular adaptations.
• Unifying features sustaining cross-resistant phenotypes across diverse cancer types remain poorly understood.

Purpose of the Study:

• To define molecular programs associated with broad drug resistance using an integrative multi-omic approach.
• To nominate compounds capable of reversing drug resistance phenotypes.

Main Methods:

• Integrated PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles.
• Utilized computational perturbagen screening to identify potential therapeutic compounds.
• Validated findings through experimental testing of nominated compounds in resistant cell lines.

Main Results:

• Identified coordinated activation of extracellular matrix remodeling, stress-adaptation, and survival signaling in resistant cells.
• NFE2L2 (Nuclear factor erythroid 2-related factor 2) emerged as a central regulatory hub linking mutations to oxidative-stress programs.
• Metabolic reprogramming was a conserved feature of resistance, correlating with shorter progression-free survival in patients.
• Rosiglitazone was identified and experimentally validated to reduce NFE2L2 activity and re-sensitize cells to chemotherapy.

Conclusions:

• Established a scalable strategy for rational phenotypic reprogramming to overcome drug resistance.
• Demonstrated the potential of targeting NFE2L2 regulatory pathways for therapeutic benefit in resistant cancers.