Related Experiment Video

Updated: Jan 17, 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

Cancer-associated Fibroblasts Confer Osimertinib Resistance in Non-small Cell Lung Cancer Cells via NRG1-mediated

Sijia Zheng1,2,3, Limin Cao1,2, Jiayi Zhang1,2

  • 1Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.

Journal of Cancer
|September 17, 2025
PubMed

Insights

Cancer-associated fibroblasts (CAFs) drive resistance to osimertinib (a lung cancer drug) by increasing cancer stemness and reducing apoptosis. CAFs secrete Neuregulin-1 (NRG1), a key factor in this resistance mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Osimertinib, a third-generation EGFR TKI, shows efficacy in EGFR-mutated NSCLC but resistance is common.
  • Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment implicated in drug resistance.
  • The specific role of CAFs in osimertinib resistance in NSCLC requires further elucidation.

Purpose of the Study:

  • To investigate the mechanism by which CAFs contribute to osimertinib resistance in non-small cell lung cancer (NSCLC).
  • To identify key molecular mediators involved in CAF-mediated osimertinib resistance.

Main Methods:

  • Co-culture systems of NSCLC cells and CAFs.
  • Assessment of cancer stemness and apoptosis.
  • Neuregulin-1 (NRG1) manipulation (recombinant NRG1, NRG1 knockdown).
  • Analysis of the HER3/AKT/NF-κB signaling pathway.
  • In vivo mouse xenograft models.

Main Results:

  • CAFs enhance NSCLC stemness and reduce osimertinib-induced apoptosis, promoting resistance.
  • CAFs secrete high levels of NRG1, which mediates their pro-resistance effects.
  • Osimertinib treatment stimulates NRG1 secretion by CAFs, potentially creating a resistance feedback loop.
  • The NRG1-mediated HER3/AKT/NF-κB pathway is crucial for CAF-driven osimertinib resistance.
  • CAFs promote tumor growth in osimertinib-treated mice.

Conclusions:

  • CAFs promote osimertinib resistance in NSCLC by enhancing stemness and reducing apoptosis via NRG1 secretion.
  • CAFs-derived NRG1 acts through the HER3/AKT/NF-κB pathway to mediate resistance.
  • Targeting CAFs-derived NRG1 presents a potential therapeutic strategy to overcome osimertinib resistance in lung cancer.
Keywords:
Cancer-associated fibroblastsHER3Lung cancerNRG1Osimertinib resistance

More Related Videos

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids08:52

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

Published on: November 22, 2021

4.6K
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

Related Concept Videos

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
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
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
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
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...
3.7K