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

Nadiia Lypova1, Lilibeth Lanceta2, Alana Gibson3

  • 1Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA. nadiia.lypova@louisville.edu.

Cancers
|May 19, 2019
PubMed

Insights

This study explored oncolytic adenovirus (OAd) responses in estrogen receptor-positive (ER+) and ER-negative (ER-) breast cancer cells resistant to palbociclib. ER+ cells showed hypersensitivity to OAd, suggesting a potential new combination therapy for ER+ breast cancer.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Metastatic breast cancer treatment faces challenges due to resistance to therapies like palbociclib.
  • Estrogen receptor-positive (ER+) and ER-negative (ER-) breast cancer exhibit distinct biological behaviors and treatment responses.
  • Oncolytic adenoviruses (OAd) show promise as anti-cancer agents, but their efficacy can be influenced by cellular context.

Purpose of the Study:

  • To investigate the differential responses of ER+ and ER- palbociclib-resistant breast cancer cells to an oncolytic adenovirus (Ad5/3-delta24).
  • To elucidate the underlying mechanisms driving OAd sensitivity or resistance in these resistant cell lines.
  • To evaluate the potential of combining OAd with palbociclib as a therapeutic strategy for ER+ breast cancer.

Main Methods:

  • Generation of ER+ and ER- palbociclib-resistant cell line models.
  • Assessment of cellular permissiveness and responses to Ad5/3-delta24.
  • Analysis of key molecular markers including type I interferon (IFN) signaling, viral entry receptor expression, and cyclin E levels.
  • Evaluation of OAd monotherapy and combination therapy with palbociclib.

Main Results:

  • ER+ palbociclib-resistant cells exhibited hypersensitivity to OAd, linked to decreased IFN signaling, increased viral entry receptors, and elevated cyclin E.
  • ER- palbociclib-resistant cells displayed resistance to OAd, associated with increased IFN signaling and reduced viral entry receptors.
  • OAd monotherapy was cytotoxic to both sensitive ER+ and ER- cells.
  • Combination of palbociclib with OAd enhanced oncolytic activity specifically in ER+ sensitive cells.

Conclusions:

  • Differential responses of ER+ and ER- cells to OAd in the context of palbociclib resistance highlight distinct cellular mechanisms.
  • The findings support a novel therapeutic approach combining oncolytic adenovirus with palbociclib for ER+ breast cancer.
  • Understanding these resistance mechanisms is crucial for developing effective combination therapies against metastatic breast cancer.
Keywords:
CDK4/6CDK4/6 inhibitorsbreast cancerestrogen receptoroncolytic adenoviruspalbociclibtherapy resistancevirotherapy

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