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Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy

1
Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA
2
The Hiram C. Polk Jr., MD, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA
3
James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, KY 40202, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 684; https://doi.org/10.3390/cancers11050684
Received: 26 April 2019 / Revised: 13 May 2019 / Accepted: 14 May 2019 / Published: 16 May 2019
(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)
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Abstract

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. View Full-Text
Keywords: palbociclib; estrogen receptor; oncolytic adenovirus; breast cancer; virotherapy; CDK4/6; CDK4/6 inhibitors; therapy resistance palbociclib; estrogen receptor; oncolytic adenovirus; breast cancer; virotherapy; CDK4/6; CDK4/6 inhibitors; therapy resistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Lypova, N.; Lanceta, L.; Gipson, A.; Vega, S.; Garza-Morales, R.; McMasters, K.M.; Chesney, J.; Gomez-Gutierrez, J.G.; Imbert-Fernandez, Y. Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy. Cancers 2019, 11, 684.

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