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Cells
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Non-Genetic Resistance to Anti-Cancer Drugs
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Non-Genetic Resistance to Anti-Cancer Drugs

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 11164

Special Issue Editor

Prof. Dr. Igor B. Roninson

E-Mail Website
Guest Editor
Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA
Interests: targeted cancer therapies; cancer drug resistance; CDK8/19; transcriptional reprogramming

Special Issue Information

Dear Colleagues,

Cancer drug resistance, a key obstacle to achieving cures, was long thought to result from a selection of rare preexisting tumor cells that carry genetic changes (mutations or gene amplification) conferring resistance. However, numerous biological and clinical observations have now painted a different picture. It has become apparent that drug resistance in most cases involves non-genetic changes in both tumor and stromal cells allowing tumors to adapt and survive drug exposure. Non-genetic plasticity and drug-induced adaptation is the key to the initial emergence of low-level resistance in a large fraction of tumor cells, enabling the subsequent survival and selection of rare genetic variants that lead to a higher level of resistance. Importantly, acquisition of non-genetic resistance was found in some cases to be preventable pharmacologically; the identification of clinically acceptable resistance-preventing agents may have a transformative impact on the outcome of cancer treatment.

This Special Issue of Cells invites both original research and review articles covering mechanistic and pharmacological aspects of non-genetic drug resistance in cancer, including resistance to conventional and targeted drugs, hormone therapies, and immune-oncological agents, in different types of solid tumors and leukemias, as well as approaches to the prevention of the emergence of non-genetic cancer drug resistance.

Prof. Igor B. Roninson
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 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

  • Drug resistance
  • Cancer therapeutics
  • Transcriptional reprogramming
  • Epigenetics

Published Papers (2 papers)

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Research

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13 pages, 1840 KiB  
Article
The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs
by Amanda C. Sharko, Chang-Uk Lim, Martina S. J. McDermott, Chuck Hennes, Kingsavanh P. Philavong, Tiffanie Aiken, Victor V. Tatarskiy, Igor B. Roninson and Eugenia V. Broude
Cells 2021, 10(1), 144; https://doi.org/10.3390/cells10010144 - 12 Jan 2021
Cited by 18 | Viewed by 3428
Abstract
Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic [...] Read more.
Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~105 cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy. Full article
(This article belongs to the Special Issue Non-Genetic Resistance to Anti-Cancer Drugs)
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Review

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34 pages, 2053 KiB  
Review
The Role of Extracellular Vesicles in the Hallmarks of Cancer and Drug Resistance
by Cristina P. R. Xavier, Hugo R. Caires, Mélanie A. G. Barbosa, Rui Bergantim, José E. Guimarães and M. Helena Vasconcelos
Cells 2020, 9(5), 1141; https://doi.org/10.3390/cells9051141 - 6 May 2020
Cited by 93 | Viewed by 7090
Abstract
Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi [...] Read more.
Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies. We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation. Special emphasis was given to the role of EVs in the transfer of drug resistant traits and to the EV cargo responsible for this transfer, both between cancer cells or between the microenvironment and tumor cells. Finally, we reviewed evidence for the increased release of EVs by drug resistant cells. A timely and comprehensive understanding of how tumor EVs facilitate tumor initiation, progression, metastasis and drug resistance is instrumental for the development of innovative EV-based therapeutic approaches for cancer. Full article
(This article belongs to the Special Issue Non-Genetic Resistance to Anti-Cancer Drugs)
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