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Molecules
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Drug Resistance in Targeted Cancer Therapy
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Drug Resistance in Targeted Cancer Therapy

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 12268

Special Issue Editors

Prof. Dr. Elisa Giovannetti

E-Mail Website
Guest Editor
Department of Medical Oncology, Cancer Center Amsterdam, VU University medical center, Amsterdam, The Netherlands
Interests: molecular mechanisms of drug activity; anticancer drugs; targeted agents; drug resistance; pharmacogenetics; pancreatic cancer; lung cancer
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Patrizia Diana

E-Mail Website
Guest Editor
Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi, 32-90123 Palermo, Italy
Interests: marine alkaloids; heterocycles; drug discovery; synthesis; bioactive compounds; antitumor activity; antibiofilm activity; and kinase inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

During the last decade, new and rationally designed drugs have been developed to neutralize specific molecules or genes involved in the development of cancer, appropriately called “targeted agents”. Most of these novel agents interact with receptors or signalling molecules, that are pivotal in tumor growth and development, and they can inhibit cancer cell proliferation, or induce programmed cell death. However, these drugs have been approved only for a limited number of malignancies, and further studies to evaluate novel applications, as well as identify biomarkers to guide these treatments are warranted. Similarly, new appropriate drug combinations might represent a major strategy to overcome the reasons for their failures, such as inherent or acquired resistance, in different tumor types.

The present issue deals with the pharmacology of the most promising compounds targeting the key oncogenic pathways implicated in the development and progression of many tumor types through multiple effects on cell cycle progression, apoptosis, and invasion. Remarkably, they use a highly overlapping repertoire of signalling adaptors and downstream pathways, and are potential targets for different drugs.

Therefore, this Special Issue will provide readers working in the basic biomedical sciences as well as clinicians a comprehensive overview of novel effective anticancer compounds, with the aim of clarifying their development, pharmacology, resistance factors, and new strategies and applications, against major tumors.

Prof. Dr. Elisa Giovannetti
Prof. Dr. Patricia Diana
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. Molecules 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

  • anticancer drugs
  • targeted agents
  • drug resistance
  • pharmacogenetics
  • kinases
  • drug discovery

Published Papers (3 papers)

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Research

16 pages, 1504 KiB  
Article
3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1H-Indole Derivatives as New Anticancer Agents in the Treatment of Pancreatic Ductal Adenocarcinoma
by Stella Cascioferro, Giovanna Li Petri, Barbara Parrino, Btissame El Hassouni, Daniela Carbone, Vincenzo Arizza, Ugo Perricone, Alessandro Padova, Niccola Funel, Godefridus J. Peters, Girolamo Cirrincione, Elisa Giovannetti and Patrizia Diana
Molecules 2020, 25(2), 329; https://doi.org/10.3390/molecules25020329 - 14 Jan 2020
Cited by 41 | Viewed by 3898
Abstract
A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity [...] Read more.
A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 µM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases. Full article
(This article belongs to the Special Issue Drug Resistance in Targeted Cancer Therapy)
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11 pages, 1952 KiB  
Article
CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage
by Btissame El Hassouni, Giulia Mantini, Benoît Immordino, Godefridus J. Peters and Elisa Giovannetti
Molecules 2019, 24(24), 4445; https://doi.org/10.3390/molecules24244445 - 04 Dec 2019
Cited by 11 | Viewed by 3330
Abstract
Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further [...] Read more.
Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. Results: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers. Full article
(This article belongs to the Special Issue Drug Resistance in Targeted Cancer Therapy)
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15 pages, 2187 KiB  
Article
The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies
by Nele Van Der Steen, Karen Zwaenepoel, Giulia Mazzaschi, Rosa A. Luirink, Daan P. Geerke, Ken Op de Beeck, Christophe Hermans, Marcello Tiseo, Paul Van Schil, Filip Lardon, Paul Germonpré, Christian Rolfo, Elisa Giovannetti, Godefridus J. Peters and Patrick Pauwels
Molecules 2019, 24(24), 4443; https://doi.org/10.3390/molecules24244443 - 04 Dec 2019
Cited by 3 | Viewed by 4491
Abstract
The c-Met receptor is a therapeutically actionable target in non-small-cell lung cancer (NSCLC), with one approved drug and several agents in development. Most suitable biomarkers for patient selection include c-Met amplification and exon-14 skipping. Our retrospective study focused on the frequency of different [...] Read more.
The c-Met receptor is a therapeutically actionable target in non-small-cell lung cancer (NSCLC), with one approved drug and several agents in development. Most suitable biomarkers for patient selection include c-Met amplification and exon-14 skipping. Our retrospective study focused on the frequency of different c-Met aberrations (overexpression, amplification and mutations) in 153 primary, therapy-naïve resection samples and their paired metastases, from Biobank@UZA. Furthermore, we determined the correlation of c-Met expression with clinicopathological factors, Epidermal Growth Factor Receptor (EGFR)-status and TP53 mutations. Our results showed that c-Met expression levels in primary tumors were comparable to their respective metastases. Five different mutations were detected by deep sequencing: three (E168D, S203T, N375S) previously described and two never reported (I333T, G783E). I333T, a new mutation in the Sema(phorin) domain of c-Met, might influence the binding of antibodies targeting the HGF-binding domain, potentially causing innate resistance. E168D and S203T mutations showed a trend towards a correlation with high c-Met expression (p = 0.058). We found a significant correlation between c-MET expression, EGFR expression (p = 0.010) and EGFR mutations (p = 0.013), as well as a trend (p = 0.057) with regards to TP53 mutant activity. In conclusion this study demonstrated a strong correlation between EGFR mutations, TP53 and c-Met expression in therapy-naïve primary resection samples. Moreover, we found two new c-Met mutations that warrant further studies. Full article
(This article belongs to the Special Issue Drug Resistance in Targeted Cancer Therapy)
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