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Pharmaceuticals
Special Issues
Epithelial Plasticity and Therapy Resistance in Cancer
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Epithelial Plasticity and Therapy Resistance in Cancer

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 October 2026 | Viewed by 2292

Special Issue Editor

Dr. Naisana Seyedasli

E-Mail Website
Guest Editor
School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia
Interests: cancer biology; stem cells; developmental biology; regenerative biology

Special Issue Information

Dear Colleagues,

A major proportion of cancers originate from the epithelial tissue. The carcinogenic process is often induced by a disturbance in the balance of epithelial homeostasis, accompanied by the dedifferentiation of the epithelial state and increased plasticity. The pathogenic plasticity of the epithelial tissue is known to be associated with cancer progression, metastasis, and resistance to therapy. This Special Issue will focus on the processes within, and mechanistic links among, epithelial plasticity, carcinogenesis, and resistance to therapy.

Dr. Naisana Seyedasli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer stem cells
  • epithelial–mesenchymal transition
  • epithelial reprogramming
  • resistance
  • drug targets
  • resistance mechanisms
  • biomarker discovery

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Published Papers (2 papers)

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Research

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18 pages, 3771 KB  
Article
VDR Decrease Enhances the Efficacy of 1,25-Dihydroxyvitamin D3 Inhibiting Gefitinib Resistance by Regulating EGFR/FASN Loop in NSCLC Cells
by Junqing Yang, Mingyu Fang, Mengjun Hou, Yalei Duan, Jiali Wang, Kaiyong Hu, Shuo Liu, Xiaoying Liu, Xiaohan Peng, Xuansheng Ding and Zhirong Jia
Pharmaceuticals 2025, 18(8), 1238; https://doi.org/10.3390/ph18081238 - 21 Aug 2025
Viewed by 1482
Abstract
Background: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, [...] Read more.
Background: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, identifying novel therapeutic approaches to combat EGFR-TKI resistance is crucial. Methods: The Cancer Genome Atlas (TCGA) database analysis and gefitinib-resistant cell lines were used to analyze VDR expression in NSCLC. Cell proliferation and apoptosis were assessed via MTT assay, colony formation assay, and flow cytometry. Immunofluorescence, qPCR, and Western blotting were used to measure mRNA and protein expression levels of VDR and other related molecules. Xenograft tumors in BALB/c nude mice were employed to investigate the effects of VDR and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on gefitinib-resistant tumors in vivo. Results: We found that VDR was significantly upregulated in EGFR-TKI-resistant NSCLC cells. Patients with high VDR expression exhibited poor prognosis. VDR knockdown significantly inhibited cell proliferation, tumor growth, and reduced gefitinib resistance, whereas VDR overexpression enhanced resistance. VDR knockdown downregulated EGFR and FASN expression. Silencing either EGFR or FASN confirmed the existence of a positive feedback regulatory loop involving VDR, EGFR, and FASN. Treatment with 1,25(OH)2D3 increased VDR levels but decreased EGFR and FASN expression. VDR knockdown significantly enhanced the inhibitory effect of 1,25(OH)2D3 on gefitinib resistance. The combination of VDR knockdown and 1,25(OH)2D3 treatment was more effective than either treatment alone in suppressing EGFR and FASN expression. Conclusions: VDR promotes NSCLC resistance to EGFR-TKIs by regulating EGFR and FASN expression through a positive feedback loop. Knocking down VDR effectively enhances the ability of 1,25(OH)2D3 to overcome gefitinib resistance, mediated by the synergistic downregulation of EGFR and FASN expression. Targeting VDR represents a potential strategy to enhance the efficacy of 1,25(OH)2D3 in overcoming EGFR-TKI resistance. Full article
(This article belongs to the Special Issue Epithelial Plasticity and Therapy Resistance in Cancer)
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Review

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28 pages, 1814 KB  
Review
Hyperglycaemia-Induced Metabolic Stress Promotes EMT-Driven Therapeutic Resistance in Cancer: Evidence of a Deleterious Feed-Forward Cycle
by Rabia Zafar, Thanh Dat Pham, Lupeuea Vakafua, Teana Reed and Naisana Seyedasli
Pharmaceuticals 2026, 19(5), 769; https://doi.org/10.3390/ph19050769 (registering DOI) - 14 May 2026
Viewed by 356
Abstract
The phenotypic plasticity of epithelial cells along the epithelial–mesenchymal (E-M) axis, or epithelial–mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour [...] Read more.
The phenotypic plasticity of epithelial cells along the epithelial–mesenchymal (E-M) axis, or epithelial–mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour metastasis. This review article investigates the potential interplay between hyperglycaemia-induced metabolic stress and EMT in the context of therapeutic resistance. The study examines a complex, multifaceted network of molecular mechanisms regulating EMT, including specialised transcription factors and signalling pathways as well as growth factors, integrins, and matrix metalloproteinases in various epithelial carcinomas. Emerging findings have demonstrated the existence of EMT hybrid states along the continuum, possessing heightened metastatic potential and distinctive metabolic signatures that play critical roles in the development of therapeutic resistance in cancer cells. Hyperglycaemia has been particularly highlighted for its potential to promote EMT-driven therapeutic resistance through various interconnected mechanisms. Elevated glucose levels induce the increased production of reactive oxygen species (ROS), activation of EMT-promoting transcription factors, and a metabolic shift towards glycolysis. This hyperglycaemic stress involves upregulation of glucose transporters and glycolytic enzymes, creating feed-forward loops that support drug efflux mechanisms and help maintain the mesenchymal phenotype. Clinical data also indicate that hyperglycaemia in OSCC patients is associated with more advanced tumour stages, more extended hospital stays, less effective treatments, and higher rates of local recurrence and distant metastasis. Overall, these insights reveal a deleterious feed-forward loop in which hyperglycaemia promotes EMT-driven therapeutic resistance, with the strongest clinical evidence in oral squamous cell carcinoma (OSCC) and supportive data from pancreatic and breast cancers. Although glycaemic control represents a promising low-risk adjunctive approach, its clinical benefit remains to be validated in prospective interventional studies. Full article
(This article belongs to the Special Issue Epithelial Plasticity and Therapy Resistance in Cancer)
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