Related Experiment Video

Updated: Jan 13, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

8.4K

EZH2-Mediated PTEN Silencing Promotes AKT-Dependent Afatinib Resistance in Radiation-Resistant Cervical Cancer Cells

Won-Hyoek Lee1,2, Seong Cheol Kim1,3, Sungchan Park1,3

  • 1Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea.

Journal of Clinical Medicine
|October 29, 2025
PubMed

Insights

Enhancer of zeste homolog 2 (EZH2) silences PTEN, causing afatinib resistance in radiation-resistant cervical cancer. Inhibiting EZH2 restores PTEN, re-sensitizing cells and tumors to afatinib, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Cervical cancer presents a significant global health challenge.
  • Treatment failure is often linked to radioresistance and drug resistance.
  • Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator involved in tumor progression.

Purpose of the Study:

  • To investigate if EZH2-mediated PTEN silencing drives afatinib resistance in radiation-resistant cervical cancer cells.
  • To explore the role of the AKT pathway in this resistance mechanism.

Main Methods:

  • Established a radioresistant cervical cancer cell line (HeLaR) via cumulative irradiation.
  • Utilized cell viability assays, clonogenic survival, methylation-specific PCR (MSP), chromatin immunoprecipitation (ChIP), and Western blot.
  • Tested EZH2, PI3K, and AKT inhibitors in combination with afatinib, and validated findings in a xenograft mouse model.

Main Results:

  • HeLaR cells showed increased EZH2 and H3K27me3, decreased PTEN, and activated AKT.
  • EZH2 inhibition normalized PTEN, reduced AKT phosphorylation, and restored afatinib sensitivity.
  • EZH2 was confirmed to silence the PTEN promoter; PI3K inhibition mimicked these effects.
  • Combined Dznep (EZH2 inhibitor) and afatinib significantly inhibited tumor growth in vivo.

Conclusions:

  • EZH2-driven PTEN suppression confers AKT-dependent afatinib resistance in radioresistant cervical cancer.
  • Targeting the EZH2-PTEN-AKT axis offers a potential strategy for overcoming combined radioresistance and chemoresistance.
  • Further preclinical and clinical validation is necessary for this therapeutic approach.
Keywords:
AKT pathwayEZH2PTENafatinibcervical cancerchemoresistanceradioresistance

More Related Videos

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

9.2K
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

10.6K

Related Concept Videos

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
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
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.6K
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
3.3K
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
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.1K