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CDK4/6 Inhibition Induces Senescence and Enhances Radiation Response by Disabling DNA Damage Repair in Oral Cavity

Nitisha Shrivastava1,2, Claudia Gutierrez Chavez2, Daniel Li3

  • 1Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Cancers
|April 13, 2023
PubMed
Abstract

Insights

Inhibiting CDK4/6 with palbociclib enhances radiation therapy for HPV(-) Oropharyngeal Squamous Cell Carcinoma (OPSCC) by increasing senescence and impairing DNA repair, improving treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • HPV(-) Oropharyngeal Squamous Cell Carcinoma (OPSCC) exhibits resistance to radiation therapy.
  • The CDKN2A gene, encoding p16INK4A, is frequently altered in OPSCC, impacting cell cycle regulation via CDK4/6 inhibition.
  • The effects of CDK4/6 inhibition on OPSCC radiosensitivity are not fully understood.

Purpose of the Study:

  • To investigate whether inhibiting CDK4/6 can enhance the response of OPSCC to radiation treatment.
  • To explore the underlying mechanisms of CDK4/6 inhibition in combination with radiation therapy.

Main Methods:

  • Utilized MTT assays and clonogenic survival analysis in OPSCC cell lines (HN5, CAL27) treated with palbociclib and radiation.
  • Examined DNA damage/repair markers (γH2AX, Rad51, Ku80) and senescence (β-gal expression).
  • Employed siRNA targeting CDK4/6 and validated findings in 3D spheroids and patient-derived organoids (CR-06, CR-18).

Main Results:

  • Combined palbociclib and radiation (P+RT) significantly reduced viability and demonstrated synergistic effects.
  • P+RT treatment increased senescence (β-gal expression) and DNA damage (γH2AX), while impairing DNA repair pathways (HR and NHEJ).
  • CDK4/6 inhibition via siRNA enhanced radiation-induced senescence, and P+RT reduced proliferation in 3D models.

Conclusions:

  • Targeting CDK4/6 in combination with radiation therapy holds promise for improving OPSCC treatment efficacy.
  • The combination therapy induces senescence and inhibits DNA damage repair mechanisms, contributing to enhanced anti-cancer effects.
Keywords:
CDK4CDK6DNA repairPD-0332991 (palbociclib)head and neck squamous cell carcinoma (HNSCC)oral cavityorganoidsradiosensitizingsenescence

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