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Cancers
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Mechanisms of Acquired Resistance to Targeted Therapy
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Mechanisms of Acquired Resistance to Targeted Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 13121

Special Issue Editor

Dr. Luca Grumolato

E-Mail Website
Guest Editor
1. Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, UNIROUEN, INSERM, Normandie Université, 76183 Rouen, France
2. Institute for Research and Innovation in Biomedicine, 76183 Rouen, France
Interests: cell signaling in cancer; targeted therapy; drug resistance; tumor heterogeneity

Special Issue Information

Dear Colleagues,

In the last few decades, extraordinary advances in our understanding of cancer biology have provided an array of new potential targets for therapy. Over the years, it has become apparent that the genetic and epigenetic aberrations that participate in oncogenic transformation are also often responsible for the addiction of tumor cells to one or few pathways for their growth and survival. Such vulnerabilities can be exploited, and a series of different compounds have been developed to tackle particular mutations or aberrantly activated signaling in cancer. Since they are specifically designed to target tumor cells, rationally based agents have less inherent toxicities compared to standard chemotherapy. Some of these drugs have revolutionized the management of certain types of tumors, including chronic myeloid leukemia, non-small lung cancer, and melanoma. However, despite very high response rates, in most cases, targeted therapies fail in the long term, and cancers relapse.

Tumors are constituted by an intricate combination of heterogeneous subclonal populations that can evolve in the presence of a selective pressure. It is now well established that therapeutic intervention promotes the emergence of resistant cells, which are either already present before the onset of the treatment or derived instead from pools of cells less sensitive to the drug, defined as tolerant or persister.

This Special Issue will highlight the various strategies and mechanisms, either genetic or epigenetic, that cancer cells use to evade targeted therapy.

Dr. Luca Grumolato
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 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. Cancers 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 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

  • targeted therapy
  • drug resistance
  • tolerant or persister cells
  • cell signaling
  • tumor relapse
  • tyrosine kinase inhibitors
  • tyrosine kinase receptor pathway

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Published Papers (3 papers)

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Research

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14 pages, 2107 KiB  
Article
Acetyl-CoA Counteracts the Inhibitory Effect of Antiandrogens on Androgen Receptor Signaling in Prostate Cancer Cells
by Peter Makhov, Rushaniya Fazliyeva, Antonio Tufano, Robert G. Uzzo, Kathy Q. Cai, Ilya Serebriiskii, Nathaniel W. Snyder, Andrew J. Andrews and Vladimir M. Kolenko
Cancers 2022, 14(23), 5900; https://doi.org/10.3390/cancers14235900 - 29 Nov 2022
Cited by 1 | Viewed by 1826
Abstract
The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) [...] Read more.
The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes and cancer signaling. In signaling, acetyl-CoA serves as the acetyl donor for acetylation, a critical post-translational modification. Acetylation affects the androgen receptor (AR) both directly and indirectly increasing expression of AR dependent genes. Our studies reveal that PC cells respond to the treatment with ARSI by increasing expression of ATP-citrate lyase (ACLY), a major enzyme responsible for cytosolic acetyl-CoA synthesis, and up-regulation of acetyl-CoA intracellular levels. Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation. Accordingly, the addition of exogenous acetyl-CoA, or its precursor acetate, augments AR transcriptional activity and diminishes the anti-AR activity of ARSI. Taken together, our findings suggest that PC cells respond to antiandrogens by increasing activity of the acetyl-coA pathway in order to reinstate AR signaling. Full article
(This article belongs to the Special Issue Mechanisms of Acquired Resistance to Targeted Therapy)
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16 pages, 1996 KiB  
Article
P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhibitor Ensartinib in Cancer Cells
by Chung-Pu Wu, Cheng-Yu Hung, Megumi Murakami, Yu-Shan Wu, Chun-Ling Lin, Yang-Hui Huang, Tai-Ho Hung, Jau-Song Yu and Suresh V. Ambudkar
Cancers 2022, 14(9), 2341; https://doi.org/10.3390/cancers14092341 - 9 May 2022
Cited by 8 | Viewed by 2360
Abstract
Ensartinib (X-396) is a promising second-generation small-molecule inhibitor of anaplastic lymphoma kinase (ALK) that was developed for the treatment of ALK-positive non-small-cell lung cancer. Preclinical and clinical trial results for ensartinib showed superior efficacy and a favorable safety profile compared to the first-generation [...] Read more.
Ensartinib (X-396) is a promising second-generation small-molecule inhibitor of anaplastic lymphoma kinase (ALK) that was developed for the treatment of ALK-positive non-small-cell lung cancer. Preclinical and clinical trial results for ensartinib showed superior efficacy and a favorable safety profile compared to the first-generation ALK inhibitors that have been approved by the U.S. Food and Drug Administration. Although the potential mechanisms of acquired resistance to ensartinib have not been reported, the inevitable emergence of resistance to ensartinib may limit its therapeutic application in cancer. In this work, we investigated the interaction of ensartinib with P-glycoprotein (P-gp) and ABCG2, two ATP-binding cassette (ABC) multidrug efflux transporters that are commonly associated with the development of multidrug resistance in cancer cells. Our results revealed that P-gp overexpression, but not expression of ABCG2, was associated with reduced cancer cell susceptibility to ensartinib. P-gp directly decreased the intracellular accumulation of ensartinib, and consequently reduced apoptosis and cytotoxicity induced by this drug. The cytotoxicity of ensartinib could be significantly reversed by treatment with the P-gp inhibitor tariquidar. In conclusion, we report that ensartinib is a substrate of P-gp, and provide evidence that this transporter plays a role in the development of ensartinib resistance. Further investigation is needed. Full article
(This article belongs to the Special Issue Mechanisms of Acquired Resistance to Targeted Therapy)
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Review

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18 pages, 1714 KiB  
Review
Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer
by Houssein Chhouri, David Alexandre and Luca Grumolato
Cancers 2023, 15(2), 504; https://doi.org/10.3390/cancers15020504 - 13 Jan 2023
Cited by 25 | Viewed by 7975
Abstract
Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence [...] Read more.
Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence of drug tolerant or resistant cells, ultimately resulting in tumor relapse. Recently, cellular barcoding strategies have arisen as a powerful tool to investigate the clonal evolution of these subpopulations in response to anti-cancer drugs. In this review, we provide an overview of the currently available treatment options for NSCLC, focusing on EGFR targeted therapy, and discuss the common mechanisms of resistance to EGFR-TKIs. We also review the characteristics of drug-tolerant persister (DTP) cells and the mechanistic basis of drug tolerance in EGFR-mutant NSCLC. Lastly, we address how cellular barcoding can be applied to investigate the response and the behavior of DTP cells upon EGFR-TKI treatment. Full article
(This article belongs to the Special Issue Mechanisms of Acquired Resistance to Targeted Therapy)
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