Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes
IntroductionDrug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes.MethodsIn this study, we applied a computational drug repositioning approach to ide...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1192208/full |
| _version_ | 1797805787018428416 |
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| author | Katharine Yu Amrita Basu Christina Yau Denise M. Wolf Hani Goodarzi Sourav Bandyopadhyay James E. Korkola Gillian L. Hirst Smita Asare Smita Asare Angela DeMichele Nola Hylton Douglas Yee Laura Esserman Laura van ‘t Veer Marina Sirota Marina Sirota |
| author_facet | Katharine Yu Amrita Basu Christina Yau Denise M. Wolf Hani Goodarzi Sourav Bandyopadhyay James E. Korkola Gillian L. Hirst Smita Asare Smita Asare Angela DeMichele Nola Hylton Douglas Yee Laura Esserman Laura van ‘t Veer Marina Sirota Marina Sirota |
| author_sort | Katharine Yu |
| collection | DOAJ |
| description | IntroductionDrug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes.MethodsIn this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival.ResultsWe found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line.ConclusionWe applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel. |
| first_indexed | 2024-03-13T05:57:20Z |
| format | Article |
| id | doaj.art-c9d670c177794b0ba2003ce13caa9f43 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-13T05:57:20Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c9d670c177794b0ba2003ce13caa9f432023-06-13T04:34:06ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-06-011310.3389/fonc.2023.11922081192208Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypesKatharine Yu0Amrita Basu1Christina Yau2Denise M. Wolf3Hani Goodarzi4Sourav Bandyopadhyay5James E. Korkola6Gillian L. Hirst7Smita Asare8Smita Asare9Angela DeMichele10Nola Hylton11Douglas Yee12Laura Esserman13Laura van ‘t Veer14Marina Sirota15Marina Sirota16Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United StatesUniversity of California, San Francisco, San Francisco, CA, United StatesUniversity of California, San Francisco, San Francisco, CA, United StatesOregon Health and Science University, Portland, OR, United StatesDepartment of Surgery, University of California, San Francisco, San Francisco, CA, United StatesBakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, United StatesQuantumLeap Healthcare Collaborative, San Francisco, CA, United StatesUniversity of Pennsylvania, Philadelphia, PA, United StatesUniversity of California, San Francisco, San Francisco, CA, United StatesUniversity of Minnesota, Minneapolis, MN, United StatesDepartment of Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United StatesBakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA, United StatesIntroductionDrug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes.MethodsIn this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival.ResultsWe found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line.ConclusionWe applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel.https://www.frontiersin.org/articles/10.3389/fonc.2023.1192208/fulldrug repositioningdrug resistanceprimary drug resistancebreast cancerdrug repurposing |
| spellingShingle | Katharine Yu Amrita Basu Christina Yau Denise M. Wolf Hani Goodarzi Sourav Bandyopadhyay James E. Korkola Gillian L. Hirst Smita Asare Smita Asare Angela DeMichele Nola Hylton Douglas Yee Laura Esserman Laura van ‘t Veer Marina Sirota Marina Sirota Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes Frontiers in Oncology drug repositioning drug resistance primary drug resistance breast cancer drug repurposing |
| title | Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes |
| title_full | Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes |
| title_fullStr | Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes |
| title_full_unstemmed | Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes |
| title_short | Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes |
| title_sort | computational drug repositioning for the identification of new agents to sensitize drug resistant breast tumors across treatments and receptor subtypes |
| topic | drug repositioning drug resistance primary drug resistance breast cancer drug repurposing |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1192208/full |
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