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

• Published in: Cancers Vol. 11; no. 5; p. 684
• Main Authors: Lypova, Nadiia, Lanceta, Lilibeth, Gibson, Alana, Vega, Stephanie, Garza-Morales, Rodolfo, McMasters, Kelly M, Chesney, Jason, Gomez-Gutierrez, Jorge G, Imbert-Fernandez, Yoannis
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16-05-2019; MDPI
• Subjects: Adenoviruses; Breast cancer; Cancer therapies; Cell culture; Cell cycle; Clinical trials; Cyclin E; Cyclin-dependent kinases; Cytotoxicity; Drug resistance; Estrogen receptors; Estrogens; Gene expression; Hypersensitivity; Immunotherapy; Infections; Interferon; Kinases; Metastases; Oncolysis; Phenotypes; Phosphorylation; Success; Tumors; oncolytic adenovirus; CDK4/6; estrogen receptor; CDK4/6 inhibitors; breast cancer; virotherapy; palbociclib; therapy resistance
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers11050684

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.