Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy
While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/5/684 |
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| author | Nadiia Lypova Lilibeth Lanceta Alana Gibson Stephanie Vega Rodolfo Garza-Morales Kelly M. McMasters Jason Chesney Jorge G. Gomez-Gutierrez Yoannis Imbert-Fernandez |
| author_facet | Nadiia Lypova Lilibeth Lanceta Alana Gibson Stephanie Vega Rodolfo Garza-Morales Kelly M. McMasters Jason Chesney Jorge G. Gomez-Gutierrez Yoannis Imbert-Fernandez |
| author_sort | Nadiia Lypova |
| collection | DOAJ |
| description | While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer. |
| first_indexed | 2024-03-12T09:39:51Z |
| format | Article |
| id | doaj.art-25c604a7cb9045bfabc6abffc0f0f0e4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:39:51Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-25c604a7cb9045bfabc6abffc0f0f0e42023-09-02T13:20:49ZengMDPI AGCancers2072-66942019-05-0111568410.3390/cancers11050684cancers11050684Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic VirotherapyNadiia Lypova0Lilibeth Lanceta1Alana Gibson2Stephanie Vega3Rodolfo Garza-Morales4Kelly M. McMasters5Jason Chesney6Jorge G. Gomez-Gutierrez7Yoannis Imbert-Fernandez8Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USAThe Hiram C. Polk Jr., MD, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USAThe Hiram C. Polk Jr., MD, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USAThe Hiram C. Polk Jr., MD, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USAThe Hiram C. Polk Jr., MD, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USAWhile clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer.https://www.mdpi.com/2072-6694/11/5/684palbociclibestrogen receptoroncolytic adenovirusbreast cancervirotherapyCDK4/6CDK4/6 inhibitorstherapy resistance |
| spellingShingle | Nadiia Lypova Lilibeth Lanceta Alana Gibson Stephanie Vega Rodolfo Garza-Morales Kelly M. McMasters Jason Chesney Jorge G. Gomez-Gutierrez Yoannis Imbert-Fernandez Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy Cancers palbociclib estrogen receptor oncolytic adenovirus breast cancer virotherapy CDK4/6 CDK4/6 inhibitors therapy resistance |
| title | Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy |
| title_full | Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy |
| title_fullStr | Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy |
| title_full_unstemmed | Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy |
| title_short | Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy |
| title_sort | targeting palbociclib resistant estrogen receptor positive breast cancer cells via oncolytic virotherapy |
| topic | palbociclib estrogen receptor oncolytic adenovirus breast cancer virotherapy CDK4/6 CDK4/6 inhibitors therapy resistance |
| url | https://www.mdpi.com/2072-6694/11/5/684 |
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