Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy
Background Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interacti...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2024
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| Online Access: | https://hdl.handle.net/1721.1/155732 |
| _version_ | 1824457959137083392 |
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| author | Leylek, Ozen Honeywell, Megan E. Lee, Michael J. Hemann, Michael T. Ozcan, Gulnihal |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Leylek, Ozen Honeywell, Megan E. Lee, Michael J. Hemann, Michael T. Ozcan, Gulnihal |
| author_sort | Leylek, Ozen |
| collection | MIT |
| description | Background
Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.
Methods
We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.
Results
Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib’s off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.
Conclusion
In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy. |
| first_indexed | 2024-09-23T09:39:40Z |
| format | Article |
| id | mit-1721.1/155732 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2025-02-19T04:18:16Z |
| publishDate | 2024 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1557322024-12-23T05:32:26Z Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy Leylek, Ozen Honeywell, Megan E. Lee, Michael J. Hemann, Michael T. Ozcan, Gulnihal Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Background Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. Methods We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. Results Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib’s off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. Conclusion In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy. 2024-07-22T16:31:54Z 2024-07-22T16:31:54Z 2024-07-20 2024-07-21T03:13:38Z Article http://purl.org/eprint/type/JournalArticle 1436-3291 1436-3305 https://hdl.handle.net/1721.1/155732 Leylek, O., Honeywell, M.E., Lee, M.J. et al. Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy. Gastric Cancer (2024). PUBLISHER_CC en 10.1007/s10120-024-01537-y Gastric Cancer Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ The Author(s) application/pdf Springer Science and Business Media LLC Springer Nature Singapore |
| spellingShingle | Leylek, Ozen Honeywell, Megan E. Lee, Michael J. Hemann, Michael T. Ozcan, Gulnihal Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy |
| title | Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy |
| title_full | Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy |
| title_fullStr | Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy |
| title_full_unstemmed | Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy |
| title_short | Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy |
| title_sort | functional genomics reveals an off target dependency of drug synergy in gastric cancer therapy |
| url | https://hdl.handle.net/1721.1/155732 |
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