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Cells
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Unlocking the Secrets Behind Drug Resistance at the Cellular Level
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Unlocking the Secrets Behind Drug Resistance at the Cellular Level

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 7426

Special Issue Editors

Dr. Sara Ricardo

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Guest Editor
UCIBIO—Applied Molecular Biosciences Unit, Toxicologic Pathology Lab at University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal
Interests: molecular pathology; cancer biology; chemoresistance; drug repurposing
Special Issues, Collections and Topics in MDPI journals
Dr. Cristina Pinto Ribeiro Xavier

E-Mail Website
Guest Editor
1. UCIBIO—Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), Gandra, Portugal
2. Associate Laboratory i4HB—Institute for Health and Bioeconomy, University Institute of Health Sciences—CESPU, Gandra, Portugal
3. i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
Interests: cancer resistance; pancreatic cancer; molecular biology; medical biotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug resistance is becoming a growing health concern. It can be developed by simple prokaryote cells to complex eukaryote cells, such as cancer cells. The World Health Organization (WHO) has identified antimicrobial resistance as one of the three significant public health challenges of the twenty-first century. Additionally, chemoresistance associated with cancer treatments is another big challenge of this century, and it is expected to increase in the coming years.

This Special Issue will contribute to the understanding of the underlying cellular mechanisms that lead to drug resistance. This issue aims to examine the mechanisms behind antibiotic resistance that are attributed to target protein alteration, integron operon network, anthropogenic activities, horizontal gene transfer, transposons and mutation in protein genes. In addition, it will investigate the ways by which drug resistance is developed in cancer, generally linked with several factors such as apoptotic pathways, immune system dysfunction, epigenetic changes and the activation of detox systems such as ROS. Other factors that can lead to chemoresistance include drug delivery problems, increased drug efflux or reduced influx, enhanced intrinsic DNA repair mechanisms and increased drug metabolism in the liver. Understanding the mechanisms behind drug resistance can trigger the development of new strategies to improve treatment efficacy in these two different disease contexts.

Dr. Sara Ricardo
Dr. Cristina Pinto Ribeiro Xavier
Guest Editors

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 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

  • molecular mechanisms
  • effective treatments
  • drug tests
  • bacterial resistance
  • chemoresistance

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Published Papers (4 papers)

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Research

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19 pages, 2883 KiB  
Article
Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer
by Kimio Yonesaka, Takashi Kurosaki, Junko Tanizaki, Hisato Kawakami, Kaoru Tanaka, Osamu Maenishi, Shiki Takamura, Kazuko Sakai, Yasutaka Chiba, Takeshi Teramura, Hiroki Goto, Eri Otsuka, Hiroaki Okida, Masanori Funabashi, Yuuri Hashimoto, Kenji Hirotani, Yasuki Kamai, Takashi Kagari, Kazuto Nishio, Kazuhiro Kakimi and Hidetoshi Hayashiadd Show full author list remove Hide full author list
Cells 2025, 14(6), 447; https://doi.org/10.3390/cells14060447 - 17 Mar 2025
Viewed by 962
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard therapies for EGFR-mutated non-small-cell lung cancer (NSCLC); however, their efficacy is inconsistent. Secondary mutations in the EGFR or other genes that lead to resistance have been identified, but resistance mechanisms have not [...] Read more.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard therapies for EGFR-mutated non-small-cell lung cancer (NSCLC); however, their efficacy is inconsistent. Secondary mutations in the EGFR or other genes that lead to resistance have been identified, but resistance mechanisms have not been fully identified. Chromosomal instability (CIN) is a hallmark of cancer and results in genetic diversity. In this study, we demonstrated by transcriptomic analysis that CIN activates the cGAS–STING signaling pathway, which leads to EGFR-TKI refractoriness in a subset of EGFR-mutated NSCLC patients. Furthermore, EGFR-mutated H1975dnMCAK cells, which frequently underwent chromosomal mis-segregation, demonstrated refractoriness to the EGFR-TKI osimertinib compared to control cells. Second, H1975dnMCAK cells exhibited activation of cGAS–STING signaling and its downstream signaling, including tumor-promoting cytokine IL-6. Finally, chromosomally unstable EGFR-mutated NSCLC exhibited enhanced epithelial–mesenchymal transition (EMT). Blockade of cGAS–STING-TBK1 signaling reversed EMT, resulting in restored susceptibility to EGFR-TKIs in vitro and in vivo. These results suggest that CIN may lead to the activation of cGAS–STING signaling in some EGFR-mutated NSCLC, resulting in EMT-associated EGFR-TKI resistance. Full article
(This article belongs to the Special Issue Unlocking the Secrets Behind Drug Resistance at the Cellular Level)
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24 pages, 12573 KiB  
Article
Overcoming Therapy Resistance in Colorectal Cancer: Targeting the Rac1 Signaling Pathway as a Potential Therapeutic Approach
by Luciano E. Anselmino, Florencia Malizia, Aylén Avila, Nahuel Cesatti Laluce, Macarena Mamberto, Lucía C. Zanotti, Cecilia Farré, Vincent Sauzeau and Mauricio Menacho Márquez
Cells 2024, 13(21), 1776; https://doi.org/10.3390/cells13211776 - 26 Oct 2024
Cited by 3 | Viewed by 1879
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide and is responsible for numerous deaths. 5-fluorouracil (5-FU) is an effective chemotherapy drug commonly used in the treatment of CRC, either as monotherapy or in combination with other drugs. However, [...] Read more.
Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide and is responsible for numerous deaths. 5-fluorouracil (5-FU) is an effective chemotherapy drug commonly used in the treatment of CRC, either as monotherapy or in combination with other drugs. However, half of CRC cases are resistant to 5-FU-based therapies. To contribute to the understanding of the mechanisms underlying CRC resistance or recurrence after 5-FU-based therapies, we performed a comprehensive study integrating in silico, in vitro, and in vivo approaches. We identified differentially expressed genes and enrichment of pathways associated with recurrence after 5-FU-based therapies. Using these bioinformatics data as a starting point, we selected a group of drugs that restored 5-FU sensitivity to 5-FU resistant cells. Interestingly, treatment with the novel Rac1 inhibitor, 1A-116, reversed morphological changes associated with 5-FU resistance.. Moreover, our in vivo studies have shown that 1A-116 affected tumor growth and the development of metastasis. All our data allowed us to postulate that targeting Rac1 represents a promising avenue for the development of new treatments for patients with CRC resistant to 5-FU-based therapies. Full article
(This article belongs to the Special Issue Unlocking the Secrets Behind Drug Resistance at the Cellular Level)
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Review

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25 pages, 1419 KiB  
Review
Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage
by Anell Fernandez, Maider Artola, Sergio Leon, Nerea Otegui, Aroa Jimeno, Diego Serrano and Alfonso Calvo
Cells 2025, 14(10), 748; https://doi.org/10.3390/cells14100748 - 20 May 2025
Viewed by 268
Abstract
Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in [...] Read more.
Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in each patient’s tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as BRCA1/BRCA2 mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients’ survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM/Chk2 or ATR/Chk1 are currently being tested in preclinical and/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM/Chk2 and ATR/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM/Chk2- or ATR/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients’ survival in modern oncology. Full article
(This article belongs to the Special Issue Unlocking the Secrets Behind Drug Resistance at the Cellular Level)
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35 pages, 2892 KiB  
Review
Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options
by Mariana Nunes, Carla Bartosch, Miguel Henriques Abreu, Alan Richardson, Raquel Almeida and Sara Ricardo
Cells 2024, 13(9), 786; https://doi.org/10.3390/cells13090786 - 4 May 2024
Cited by 6 | Viewed by 3764
Abstract
Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that [...] Read more.
Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets. Full article
(This article belongs to the Special Issue Unlocking the Secrets Behind Drug Resistance at the Cellular Level)
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