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Targeting WEE1 Inhibits Growth of Breast Cancer Cells That Are Resistant to Endocrine Therapy and CDK4/6 Inhibitors

Yassi Fallah1, Diane M Demas1, Lu Jin1

  • 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States.

Frontiers in Oncology
|July 19, 2021
PubMed

Insights

Targeting the G2 checkpoint with WEE1 inhibitors like Adavosertib shows promise for treating endocrine-resistant estrogen receptor-positive (ER+) breast cancer by inducing cell death and DNA damage in resistant cells.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • Estrogen receptor-positive (ER+) breast cancer often develops resistance to antiestrogen therapies.
  • CDK4/6 inhibitors are used for resistant tumors, but intrinsic resistance occurs in 20% of cases.
  • Long-term estrogen deprivation (LTED) models mimic endocrine resistance and CDK4/6 inhibitor resistance.

Purpose of the Study:

  • To investigate the potential of targeting the G2 cell cycle checkpoint in endocrine-resistant ER+ breast cancer.
  • To evaluate the efficacy of WEE1 inhibition using Adavosertib (AZD1775) in LTED breast cancer cells.

Main Methods:

  • Generation of LTED endocrine-resistant ER+ breast cancer cells (MCF7, T47D) resistant to CDK4/6 inhibitors.
  • Inhibition of WEE1, a G2 checkpoint regulator, using Adavosertib (AZD1775).
  • Assessment of cell proliferation, G2/M arrest, apoptosis, and DNA double-strand breaks (gamma-H2AX) in sensitive and resistant cells.

Main Results:

  • Adavosertib significantly decreased cell proliferation in resistant cells compared to sensitive cells.
  • WEE1 inhibition led to increased G2/M arrest and apoptosis in resistant LTED cells.
  • Elevated gamma-H2AX levels indicated increased DNA double-strand breaks in resistant cells treated with Adavosertib.

Conclusions:

  • Targeting the G2 checkpoint via WEE1 inhibition is a potential therapeutic strategy for endocrine-resistant ER+ breast cancer.
  • Adavosertib demonstrates efficacy in inducing cell death and DNA damage in cells resistant to standard therapies.
  • WEE1 inhibition may overcome intrinsic resistance to CDK4/6 inhibitors in ER+ breast cancer.
Keywords:
AZD1775CDK4/6 inhibitorsWEE1drug resistanceendocrine therapyestrogen receptor positive breast cancerribociclib

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