Dataset Information

Research on the mechanism by which cancer-associated fibroblasts (CAFs) promote EGFR-TKI resistance in non-small cell lung cancer (NSCLC) via secretory proteins

ABSTRACT: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major clinical challenge in the targeted therapy of non-small cell lung cancer (NSCLC), yet its underlying mechanisms are poorly understood. The tumor microenvironment (TME), which provides a supportive niche for cancer cell survival and progression, plays a pivotal role in NSCLC drug resistance. Our preliminary studies revealed that activated cancer-associated fibroblasts (CAFs) in the TME induce EGFR-TKI resistance in lung cancer cells by secreting neuregulin-1 (NRG1). Further investigations identified STAT3 as a key regulator of CAF activation and secretory function. We thus hypothesize that inhibiting STAT3 activation may block CAF-mediated secretion, thereby reversing EGFR-TKI resistance in lung cancer.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zhe Liu

PROVIDER: PXD064318 | iProX | Mon May 26 00:00:00 BST 2025

REPOSITORIES: iProX

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Publications

STAT3 mediates CAF-induced osimertinib resistance via regulating protein secretion in non-small cell lung cancer.

Fan Xuchen X Wu Sheng S Wu Honglong H Huang Yingying Y Tong Xuhui X Yu Meiling M Liu Zhe Z

Frontiers in pharmacology 20250709

<h4>Introduction</h4>EGFR-TKI resistance is an important factor limiting the clinical application of targeted drugs in NSCLC, but the mechanism remains unclear. The tumor microenvironment is the internal environment for cancer cells to survive, and it plays an important role in tumor resistance.<h4>Methods</h4>In vitro assays: CCK-8 assay, wound healing, Transwell and Colony formation assay. Protein expression analyzed via Western blot. In vivo antitumor efficacy assessed by xenograft study. Tar ...[more]

PMID: 40703348

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Project description:Bidkhori2012 - EGFR signalling in NSCLC The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in NSCLA cells. Created by The MathWorks, Inc. SimBiology tool, Version 3.3 This model is described in the article: Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression. Bidkhori G, Moeini A, Masoudi-Nejad A PloS one [2012, 7(10):e48004] Abstract: EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib. This model is hosted on BioModels Database and identified by: MODEL1304020001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Bidkhori2012 - normal EGFR signalling The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in normal cells. Created by The MathWorks, Inc. SimBiology tool, Version 3.3 This model is described in the article: Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression. Bidkhori G, Moeini A, Masoudi-Nejad A PloS one [2012, 7(10):e48004] Abstract: EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib. This model is hosted on BioModels Database and identified by: MODEL1304020000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Research on the mechanism by which cancer-associated fibroblasts (CAFs) promote EGFR-TKI resistance in non-small cell lung cancer (NSCLC) via secretory proteins

Publications

STAT3 mediates CAF-induced osimertinib resistance via regulating protein secretion in non-small cell lung cancer.

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