Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy [preprint]
Student AuthorsMegan Honeywell
UMass Chan AffiliationsMorningside Graduate School of Biomedical Sciences
Program in Molecular Medicine
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AbstractThe rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib is the same as SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib's off-target effect that inhibits ABCG2 but not its on-target effect on EGFR. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions.
SourceLeylek O, Honeywell ME, Lee MJ, Hemann MT, Ozcan G. Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy. bioRxiv [Preprint]. 2023 Nov 19:2023.10.07.561351. doi: 10.1101/2023.10.07.561351. PMID: 37873383; PMCID: PMC10592690.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52798
NotesThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
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Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.; Attribution-NonCommercial-NoDerivatives 4.0 International