Purpose: Resistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype.
Experimental Design: Because the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non-small cell lung cancer (NSCLC) cell lines.
Results: Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity.In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy.
Conclusions: This result supports the role of the Hh pathway in mediating resistance to anti-EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-3319 | DOI Listing |
Int J Surg
January 2025
Carcinoma Department of Traditional Chinese Medicine, Dianjiang People's Hospital of Chongqing, Chongqing, PR China.
The widespread adoption of high-resolution computed tomography (CT) screening has led to increased detection of small pulmonary nodules, necessitating accurate localization techniques for surgical resection. This review examines the evolution, efficacy, and safety of various localization methods for small pulmonary nodules. Studies focusing on localization techniques for pulmonary nodules ≤30 mm in diameter were included, with emphasis on technical success rates and complication profiles.
View Article and Find Full Text PDFJAMA
January 2025
CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.
Importance: Essential thrombocythemia, a clonal myeloproliferative neoplasm with excessive platelet production, is associated with an increased risk of thrombosis and bleeding. The annual incidence rate of essential thrombocythemia in the US is 1.5/100 000 persons.
View Article and Find Full Text PDFCell Mol Life Sci
January 2025
Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.
Non-small cell lung cancer (NSCLC) has emerged as one of the most prevalent malignancies worldwide. N6-methyladenosine (mA) methylation, a pervasive epigenetic modification in long noncoding RNAs (lncRNAs), plays a crucial role in NSCLC progression. Here, we report that mA modification and the expression of the lncRNA stem cell inhibitory RNA transcript (SCIRT) was significantly upregulated in NSCLC tissues and cells.
View Article and Find Full Text PDFJ Med Chem
January 2025
Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression in NSCLC cells. In this work, to address the deficiency that sesquiterpene lactone containing α-methylene-γ-lactone moiety was rapidly metabolized by endogenous nucleophiles, series of novel thioether derivatives were designed and synthesized based on a reactive oxygen species (ROS)-triggered prodrug strategy. Among them, prodrug exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS.
View Article and Find Full Text PDFPathol Int
January 2025
Department of Cancer Pathology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
Recent studies suggest that lung adenocarcinoma cells are closely associated with the tumorigenesis of large-cell neuroendocrine carcinoma via cellular transformation. However, morphological evidence, along with genetic abnormalities before, during, and after transformation, is quite limited. We present here a case of combined large-cell neuroendocrine carcinoma and adenocarcinoma exhibiting acinar and solid patterns.
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