Related Experiment Video

Updated: May 24, 2025

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

3.9K

Novel Approach to Overcome Osimertinib Resistance Using Bromodomain and Extra-Terminal Domain Inhibitors

Yosuke Miyashita1,2, Ken Tajima1,2, Kenta Izumi1,2

  • 1Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Cancer Science
|March 4, 2025
PubMed

Insights

This study reveals that fibroblast growth factor 1 (FGF1) drives resistance to osimertinib in lung cancer by altering chromatin. Combining bromodomain inhibitors with osimertinib overcomes this resistance, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Osimertinib is a first-line treatment for EGFR-mutated lung cancer, but resistance mechanisms are not fully understood.
  • Epigenetic dysregulation is suspected in drug resistance, yet specific pathways remain unclear.

Purpose of the Study:

  • To investigate the role of epigenetics in osimertinib resistance in lung cancer.
  • To explore the therapeutic potential of targeting epigenetic modifications to overcome osimertinib resistance.

Main Methods:

  • Established osimertinib-resistant lung cancer cell lines.
  • Utilized assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing to analyze chromatin accessibility and gene expression.
  • Investigated the role of fibroblast growth factor 1 (FGF1) and histone modifications.
  • Tested combination therapy with bromodomain and extra-terminal domain (BET) inhibitors and osimertinib in vitro and in vivo.

Main Results:

  • Significant changes in chromatin accessibility were observed in resistant cells.
  • FGF1 was identified as a resistance-related gene regulated by histone modifications.
  • FGF1 overexpression induced osimertinib resistance, while its suppression attenuated resistance.
  • Combination therapy with BET inhibitors and osimertinib effectively overcame resistance in cell lines and mouse xenograft models.
  • Increased FGF1 expression was found in clinical osimertinib-resistant samples.

Conclusions:

  • Epigenetic alterations, specifically involving histone modifications regulating FGF1, play a crucial role in osimertinib resistance.
  • Targeting histone modifications with BET inhibitors represents a promising novel strategy to overcome osimertinib resistance in lung cancer.
  • FGF1 is a potential therapeutic target for overcoming osimertinib resistance.
Keywords:
ATAC‐seqEpigenomicsFGF1lung neoplasmsosimertinib

More Related Videos

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib09:38

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

Published on: June 26, 2019

7.9K
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.1K

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...
7.4K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.2K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
4.8K