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CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid

Jaime M Pita1, Eric Raspé1, Katia Coulonval1

  • 1Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) and Université Libre de Bruxelles (ULB)-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium.

Frontiers in Endocrinology
|November 15, 2023
PubMed
Abstract

Insights

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) show promise for treating advanced thyroid cancers, particularly when combined with BRAF/MEK inhibitors. Detecting CDK4 phosphorylation can identify patients who will respond to CDK4/6i therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • CDK4/6 inhibitors (CDK4/6i) are standard for advanced Estrogen Receptor-positive breast cancers.
  • CDK4/6i are being investigated for other cancers, often in combination therapies.
  • T172-phosphorylation of CDK4 is critical for its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment, and sensitivity to CDK4/6i.
  • Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas are lethal malignancies with limited treatment options.
  • Molecular evidence suggests CDK4/6i could be effective against advanced thyroid cancers.

Purpose of the Study:

  • To investigate the role of CDK4 phosphorylation in thyroid carcinomas.
  • To assess the sensitivity of thyroid cancer cells and tissues to CDK4/6 inhibitors.
  • To evaluate the efficacy of combining CDK4/6 inhibitors with BRAF/MEK inhibitors in thyroid cancer models.

Main Methods:

  • Analysis of CDK4 phosphorylation status in 98 fresh-frozen thyroid tumor tissues and 21 cell lines using two-dimensional gel electrophoresis.
  • RNA sequencing and immunohistochemistry for sub-cohort characterization.
  • Assessment of sensitivity to palbociclib and abemaciclib using BrdU incorporation and viability assays.
  • Evaluation of drug combinations (CDK4/6i with dabrafenib/trametinib) via western blot, immunoprecipitation, and clonogenic assays.

Main Results:

  • CDK4 phosphorylation was detected in most thyroid carcinomas (all well-differentiated, 19/20 PDTC, 16/23 ATC) and cell lines (18/21).
  • Absence of CDK4 phosphorylation correlated with CDK4/6i insensitivity and high p16 levels.
  • RB1 defects were not found in all tumors lacking CDK4 phosphorylation.
  • An 11-gene expression signature identified likely unresponsive tumors lacking CDK4 phosphorylation.
  • Palbociclib combined with dabrafenib/trametinib led to complete and permanent proliferation arrest in cell lines, preventing resistance mechanisms.

Conclusions:

  • CDK4/6i, especially in combination with anti-BRAF/MEK therapies, represent a promising treatment strategy for advanced thyroid tumors.
  • An 11-gene predictor combined with p16/KI67 evaluation can identify CDK4/6i-insensitive patients.
  • These patients may be better candidates for immediate chemotherapy.
Keywords:
ATCCDK4 Thr172-phosphorylationPDTCbiomarkersdabrafenibpalbociclibtrametinib

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