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Cancer-associated fibroblasts strengthen cell proliferation and EGFR TKIs resistance through aryl hydrocarbon receptor dependent signals in non-small cell lung cancer.

ABSTRACT: The tumor microenvironment is a dynamic cellular milieu that interacts with cancer cells and promotes tumor progression and metastasis. However, the specific mechanisms by which the tumor microenvironment impacts cancer cells' behaviors remain poorly understood. In this study, enriched cancer-associated fibroblasts (CAFs) were observed in tumor tissues isolated from epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) resistant non-small cell lung cancer (NSCLC) patients. CAFs isolated from tumor tissues were capable of producing tryptophan metabolite kynurenine (Kyn), which significantly increased the proliferation and EGFR TKIs resistance of NSCLC cells. In this study, it was further observed that the activation of tryptophan 2,3-dioxygenase (TDO) in CAFs, resulted in the enhanced capability of tryptophan metabolism in them compared to normal fibroblasts. As a result, Kyn produced by CAFs facilitated the up-regulation of Aryl Hydrocarbon Receptor (AhR) signals in NSCLC, thereby resulting in the downstream ATK and ERK signaling pathways activation. Finally, inhibition of AhR signals efficiently prevented tumor growth and development of EGFR TKIs resistance, eventually improved the outcome of EGFR TKIs, and described a promising therapeutic strategy for NSCLC.

SUBMITTER: Feng H

PROVIDER: S-EPMC9281029 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cancer-associated fibroblasts derived from EGFR-TKI-resistant tumors reverse EGFR pathway inhibition by EGFR-TKIs.

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| S-EPMC3445427 | biostudies-literature

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Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non-Small Cell Lung Cancer.

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| S-EPMC8756122 | biostudies-literature

EGFR-plasma mutations in prognosis for non-small cell lung cancer treated with EGFR TKIs: A meta-analysis.

Project description:BackgroundThe plasma-based epidermal growth factor receptor (EGFR) mutation testing is approved recently to use in clinical practice. However, it has not been used as a prognostic marker yet because of contradictory results.AimThis meta-analysis aims to clarify the role of the EGFR-plasma test in prognosis for non-small cell lung cancer (NSCLC) who have mutant tumors and receive EGFR tyrosine kinase inhibitors (TKIs).Methods and resultsThe PubMed/MEDLINE, Web of Science, Cochrane Library, and Google Scholar databases were searched for relevant studies by April 10, 2021. The hazard ratio (HR) from reports was extracted and used to assess the correlation of EGFR-plasma status with progression-free survival (PFS) and overall survival (OS). A total of 35 eligible studies with 4106 patients were enrolled in the final analysis. Patients with concurrent EGFR mutations in pretreatment plasma have shorter PFS (HR = 2.00, 95% confidence interval [CI]: 1.73-2.31, p < .001) and OS time (HR = 2.31, 95% CI: 1.89-2.83, p < .001) compared to the tumor-only mutation cases. Besides, the persistence of EGFR-activating mutations in post-treatment plasma is associated with worse PFS (HR = 3.84, 95% CI: 2.96-4.99, p < .001) and OS outcome (HR = 3.22, 95% CI: 2.35-4.42, p < .001) compared to others. Notably, the prognostic value of the EGFR-plasma test is also validated in treatment with third-generation EGFR TKI and significance regardless of different detection methods.ConclusionThe presence of EGFR-plasma mutations at pretreatment and after EGFR TKI initiation is the worse prognostic factor for PFS and OS in NSCLC.

| S-EPMC9351650 | biostudies-literature

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