Related Experiment Video

Updated: Jan 9, 2026

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

11.4K

Inhibition of CDKs Enhances the Efficacy of Anti-EGFR Therapy in Chordoma

Tianna Zhao1, Riccardo Serra1, Michelle Guo1

  • 1Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Molecular Cancer Therapeutics
|December 4, 2025
PubMed

Insights

Combining cyclin-dependent kinase (CDK) inhibitors THZ1 or TG02 with afatinib significantly enhances anti-tumor activity in chordoma models. This novel combination therapy targets key growth pathways, offering a promising strategy for chordoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Chordoma exhibits incomplete response to epidermal growth factor receptor (EGFR) blockade.
  • High expression of cyclin-dependent kinases (CDK) 7 and 9 is observed in chordoma.
  • Novel therapeutic strategies are needed to overcome resistance to current treatments.

Purpose of the Study:

  • To investigate the efficacy of CDK inhibitors THZ1 and TG02, alone and in combination with EGFR inhibitor afatinib, in preclinical chordoma models.
  • To elucidate the molecular mechanisms underlying the combination therapy's anti-tumor effects.
  • To evaluate the therapeutic potential of this combination strategy for chordoma patients.

Main Methods:

  • Chordoma cell lines and patient-derived xenografts were treated with THZ1, TG02, and afatinib as single agents or in combination.
  • Cell viability, proliferation, colony formation, and apoptosis were assessed.
  • Western blotting was used to analyze protein expression and phosphorylation, including RNA polymerase II (POL II) and MCL1.
  • Tumor growth inhibition was evaluated in vivo.

Main Results:

  • Monotherapy with THZ1, TG02, or afatinib reduced chordoma cell viability and induced apoptosis.
  • Combination therapy with THZ1/afatinib and TG02/afatinib demonstrated enhanced anti-tumor activity compared to single agents.
  • CDK inhibitors inhibited POL II phosphorylation, leading to decreased brachyury transcription, an effect amplified by afatinib.
  • Combination treatment further reduced MCL1 expression.
  • Co-treatments showed superior tumor growth inhibition in both cell line- and patient-derived xenograft models.

Conclusions:

  • THZ1 and TG02 significantly enhance the efficacy of afatinib in preclinical chordoma models.
  • The combination therapy targets key oncogenic pathways, including brachyury transcription and MCL1 expression.
  • This CDK inhibitor and EGFR inhibitor combination represents a promising novel therapeutic strategy for chordoma.

More Related Videos

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.8K
An Immunofluorescent Method for Characterization of Barrett’s Esophagus Cells08:54

An Immunofluorescent Method for Characterization of Barrett’s Esophagus Cells

Published on: July 20, 2014

14.4K

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.5K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.7K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
6.2K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.6K
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
3.3K