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Updated: Oct 1, 2025

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
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Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen

Lucia Viganò1, Alberta Locatelli1, Adele Ulisse1

  • 1Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 7, 2022
PubMed
Abstract

Insights

Combining endocrine therapy, HER2-blockade, and CDK4/6 inhibition offers a chemotherapy-free option for ER+/HER2+ breast cancer. This approach induces senescence and overcomes resistance mechanisms, suggesting a refined treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) signaling pathways crosstalk in ER-positive (ER+)/HER2-positive (HER2+) breast cancer.
  • This interplay drives tumor growth via mitogenic signals converging on the Cyclin-D1/CDK4/6 complex.

Purpose of the Study:

  • To investigate the cross-talk between ER and RTK signaling in ER+/HER2+ breast cancer.
  • To evaluate the efficacy of a combination therapy including endocrine therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6 inhibition (palbociclib) – termed PFHPert.
  • To assess the impact of this combination on cancer cell proliferation, resistance mechanisms, and senescence induction.

Main Methods:

  • In vitro studies using ER+/HER2+, HER2low, and ER-negative (ER-)/HER2+ breast cancer cell lines treated with PFHPert.
  • Pharmacodynamic and gene-expression analyses over 72 hours and 6 days post-treatment.
  • Assessment of Ki67 downregulation and senescence-related gene expression in patients from the NA-PHER2 trial (NCT02530424) treated with neoadjuvant PFHPert.

Main Results:

  • PFHPert demonstrated additive or synergistic antiproliferative activity in vitro, interfering with RTKs/Akt/MTORC1 resistance pathways and inducing sustained senescence.
  • Unexpected synergistic effects were observed in HER2low breast cancer cells.
  • In patients, Ki67 downregulation correlated significantly with upregulation of senescence-related genes.
  • MTORC1 pathway activation was associated with high Ki67 levels at surgery.

Conclusions:

  • The PFHPert combination offers an effective chemotherapy-free regimen for ER+/HER2+ breast cancer by bypassing resistance mechanisms through Rb cotargeting and promoting senescence.
  • MTORC1 pathway activation and RTK functional activation represent potential escape mechanisms.
  • Understanding sensitivity and resistance patterns provides insights for refining future breast cancer treatment strategies.

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