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Biomedicines
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Drug Resistance and Novel Targets for Cancer Therapy—Second Edition
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Drug Resistance and Novel Targets for Cancer Therapy—Second Edition

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 14213

Special Issue Editors

Dr. Bruno Kaufmann Robbs

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Guest Editor
Instituto de Saúde de Nova Friburgo, Universidade Federal Fluminense, Nova Friburgo, Brazil
Interests: natural product; organic synthesis; cancer drugs; chemotherapeutic molecular targets
Special Issues, Collections and Topics in MDPI journals
Dr. Fernando de Carvalho da Silva

E-Mail Website
Guest Editor
Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Interests: organic synthesis; medicinal chemistry; naphthoquinones; triazoles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug resistance is a complex phenomenon resulting from one or more mechanisms which render cells resistant to anticancer drugs. Molecular hallmarks of cancer and therapeutics against drug resistance mechanisms are the leading targets for cancer treatment. Molecular targeted therapy is gaining attraction due to its specificity to cancer while sparing normal cells. Despite this, drug resistance still representsa major obstacle that limits sustained clinical benefits not only to targeted cancer therapies, but also conventional chemotherapy. Notably, while some cancer patients do not respond to anticancer drugs due to primary resistance, even responders might eventually relapse following acquired resistance.

 In this context, we are proposing a new Special Issue encompassing these two major molecular pathways involved in cancer treatment such as the determinations of new cancer related molecular targets, development of drugs that block them and drugs that aims resistance to treatment. We invite innovative research papers and review articles discussing new molecular targets or anticancer drugs. We encourage articles related, but not restricted to Apoptosis Induction, Proliferative Signaling, Migration, Angiogenesis, Metastasis, Immune Checkpoint, Tumor Vaccine Related Targets, Chimeric Antigen Receptor T-Cell or their possible drug resistance mechanisms. Therefore, this special issue is aimed to approach novel molecular targets, their bullets and possible resistance mechanisms that might be targeted to potentiate more durable and effective responses for cancer therapy.

Dr. Bruno Kaufmann Robbs
Dr. Fernando de Carvalho da Silva
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. Biomedicines 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 2600 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
  • drug resistance
  • targeted therapy
  • conventional chemotherapy
  • natural products
  • molecular targets
  • cancer hallmarks
  • therapeutic agents

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Related Special Issue

Published Papers (7 papers)

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Research

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16 pages, 12926 KiB  
Article
B Cell Activating Factor Induces Drug Resistance in Hairy Cell Leukemia Variant
by Claire Fritz, Daniel Feinberg, Akshaya Radhakrishnan, Kayla Klatt, E. Ricky Chan, Philip Rock, Richard Burack and Reshmi Parameswaran
Biomedicines 2025, 13(4), 890; https://doi.org/10.3390/biomedicines13040890 - 7 Apr 2025
Viewed by 354
Abstract
Background: Chemoresistance is an existing challenge faced in the treatment of the hairy cell leukemia variant (HCL-v). Classical hairy cell leukemia (HCL-c) is very sensitive to the standard of care with purine nucleoside analogs (PNAs) cladribine (cDa) and pentostatin. However, almost half of [...] Read more.
Background: Chemoresistance is an existing challenge faced in the treatment of the hairy cell leukemia variant (HCL-v). Classical hairy cell leukemia (HCL-c) is very sensitive to the standard of care with purine nucleoside analogs (PNAs) cladribine (cDa) and pentostatin. However, almost half of these patients eventually become less sensitive to chemotherapy and relapse. HCL-variant (HCL-v) is a biologically distinct entity from HCL-c that is not sensitive to frontline PNA therapy, and this treatment is not recommended for these patients. To address these treatment challenges, we investigated the role of B-cell activating factor (BAFF) in promoting HCL-v cell chemoresistance. Methods: Flow cytometry and quantitative PCR were used to measure the levels of BAFF and its receptors. To determine BAFF activated pathways in HCL-c and HCL-v, the Bonna-12 HCL-c cell line or HCL-v patient-derived cancer cells were stimulated with recombinat BAFF and activation of common BAFF-activated pathways, including the nonclassical nuclear factor kappa B (NF-κB) pathway, the Extracellular Signal-Regulated Kinase (Erk) and phosphatidylinositol-3 (PI-3) kinase (PI3K)/AKT serine/threonine kinase (AKT) pathways were measured by western blotting. To test whether BAFF signaling promotes chemoresistance in HCL-v, we stimulated patient-derived HCL-v cells with BAFF and performed RNA sequencing. Lastly, to confirm the functional implications of BAFF signaling in HCL-v, we treated patient-derived HCL-v cells with exogenous BAFF before treatment with cladribine. Results: We found that HCL-v patient-derived cancer cells express receptors of BAFF at varying degrees and express relatively lower levels of membrane-bound BAFF ligand expression. BAFF stimulation of these cells resulted in substantial activation of the nonclassical NF-κB pathway, which is known to promote anti-apoptotic and pro-survival effects in B-cell cancers. Conversely, in the Bonna-12 cell line, we observed constitutive activation of the nonclassical NF-κB pathway. Through RNA sequencing, we found that BAFF upregulates a myriad of genes that are known to promote chemoresistance in various cancers, including IL1, CXCL1/2, CXCL5, CXCL8, TRAF3, and PTGS2. Lastly, we found that BAFF protects these cells from cladribine-induced cell death in vitro. Conclusions: We conclude that BAFF provides chemo-protection in HCL-v cells by activating nonclassical NF-κB signaling, which results in the upregulation of multiple pro-survival or anti-apoptotic genes. Our results highlight an important role of BAFF in HCL-v resistance to chemotherapy and suggest that the BAFF blockade may enhance the chemosensitivity to PNAs in drug-resistant HCL-v patients. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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12 pages, 1636 KiB  
Article
Real-World Analysis of Adherence to Abemaciclib and Endocrine Therapy in Women with HR+/HER2− Breast Cancer
by Maria Rosaria Valerio, Federica Martorana, Maria Vita Sanò, Daniela Sambataro, Gianmarco Motta, Lucia Motta, Giuliana Pavone, Vittorio Gebbia and Giuseppa Scandurra
Biomedicines 2025, 13(3), 546; https://doi.org/10.3390/biomedicines13030546 - 21 Feb 2025
Viewed by 910
Abstract
Background: Adherence to oral anticancer therapies among breast cancer patients is an often-overlooked issue. A lack of patient compliance can be caused by several factors, and may hinder the efficacy of prescribed medication, leading to a shorter than expected survival. In this context, [...] Read more.
Background: Adherence to oral anticancer therapies among breast cancer patients is an often-overlooked issue. A lack of patient compliance can be caused by several factors, and may hinder the efficacy of prescribed medication, leading to a shorter than expected survival. In this context, few data about adherence to CDK4/6 inhibitors in real-world practice are available. We report here the results of a retrospective analysis of adherence to abemaciclib plus endocrine therapy in a cohort of women with hormone receptor-positive (HR+), epidermal growth factor 2 negative (HER2−) breast cancer. Methods: Abemaciclib adherence was computed as the ratio between the total number of cycles/months that medication was supplied and the months between the first and the last prescription. The proportion of Days Covered (PDC) ranged from 0 to 1. A score of 0.8 (i.e., 80% adherence rate) was the cutoff used to classify the patients as adherent (0.8 ≤ PDC ≤ 1) or non-adherent (0 ≤ PDC < 0.8). The received dose intensity was also calculated. Results: The abemaciclib pharmacy claims of 100 women with HR+/HER2− breast cancer were retrieved. Most patients (91%) were treated in the advanced setting. Abemaciclib was more frequently taken with an aromatase inhibitor (63%) than with fulvestrant (27%). In this population, the adherence rate was high (92.25% + 1.939 SD). The proportion of non-adherent patients taking abemaciclib with PDC <0.8 was 12%. There was a significative correlation between the occurrence of side effects and the use of <5 drugs for non-oncological illnesses, probably reflecting concomitant non-oncological diseases. Conclusions: Adherence to abemaciclib-based therapy is high in a real-life setting, pending the adequate and proactive management of patients. The careful evaluation of patients and detailed information about expected adverse events are essential to ensure adherence to this antineoplastic agent. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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22 pages, 10397 KiB  
Article
Mannich Base Derived from Lawsone Inhibits PKM2 and Induces Neoplastic Cell Death
by Lucas Rubini-Dias, Tácio V. A. Fernandes, Michele P. de Souza, Déborah Hottz, Afonso T. Arruda, Amanda de A. Borges, Gabriel Ouverney, Fernando de C. da Silva, Luana da S. M. Forezi, Gabriel Limaverde-Sousa and Bruno K. Robbs
Biomedicines 2024, 12(12), 2916; https://doi.org/10.3390/biomedicines12122916 - 21 Dec 2024
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Abstract
Background/Objectives: Pyruvate kinase M2, a central regulator of cancer cell metabolism, has garnered significant attention as a promising target for disrupting the metabolic adaptability of tumor cells. This study explores the potential of the Mannich base derived from lawsone (MB-6a) to [...] Read more.
Background/Objectives: Pyruvate kinase M2, a central regulator of cancer cell metabolism, has garnered significant attention as a promising target for disrupting the metabolic adaptability of tumor cells. This study explores the potential of the Mannich base derived from lawsone (MB-6a) to interfere with PKM2 enzymatic activity both in vitro and in silico. Methods: The antiproliferative potential of MB-6a was tested using MTT assay in various cell lines, including SCC-9, Hep-G2, HT-29, B16-F10, and normal human gingival fibroblast (HGF). The inhibition of PKM2 mediated by MB-6a was assessed using an LDH-coupled assay and by measuring ATP production. Docking studies and molecular dynamics calculations were performed using Autodock 4 and GROMACS, respectively, on the tetrameric PKM2 crystallographic structure. Results: The Mannich base 6a demonstrated selective cytotoxicity against all cancer cell lines tested without affecting cell migration, with the highest selectivity index (SI) of 4.63 in SCC-9, followed by B16-F10 (SI = 3.9), Hep-G2 (SI = 3.4), and HT-29 (SI = 2.03). The compound effectively inhibited PKM2 glycolytic activity, leading to a reduction of ATP production both in the enzymatic reaction and in cells treated with this naphthoquinone derivative. MB-6a showed favorable binding to PKM2 in the ATP-bound monomers through docking studies (PDB ID: 4FXF; binding affinity scores ranging from −6.94 to −9.79 kcal/mol) and MD simulations, revealing binding affinities stabilized by key interactions including hydrogen bonds, halogen bonds, and hydrophobic contacts. Conclusions: The findings suggest that MB-6a exerts its antiproliferative activity by disrupting cell glucose metabolism, consequently reducing ATP production and triggering energetic collapse in cancer cells. This study highlights the potential of MB-6a as a lead compound targeting PKM2 and warrants further investigation into its mechanism of action and potential clinical applications. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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17 pages, 4024 KiB  
Article
Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies
by Federica Malighetti, Matteo Villa, Mario Mauri, Simone Piane, Valentina Crippa, Ilaria Crespiatico, Federica Cocito, Elisa Bossi, Carolina Steidl, Ivan Civettini, Chiara Scollo, Daniele Ramazzotti, Carlo Gambacorti-Passerini, Rocco Piazza, Luca Mologni and Andrea Aroldi
Biomedicines 2024, 12(12), 2819; https://doi.org/10.3390/biomedicines12122819 - 12 Dec 2024
Viewed by 1200
Abstract
Background: Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade [...] Read more.
Background: Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade the immune system, partly through tumor-associated macrophages (TAMs) that facilitate immune escape. Cancer cells use “don’t eat me” signals (DEMs), such as CD47, to resist TAMs-mediated phagocytosis. TKIs may upregulate pro-phagocytic stimuli (i.e., calreticulin, CALR), suggesting a potential therapeutic benefit in combining TKIs with an anti-CD47 monoclonal antibody (mAb). However, the impact of this combination on both TKIs-sensitive and resistant ALK+ tumors requires further investigation. Methods: A panel of TKIs-sensitive and resistant ALK+ cancer subtypes was assessed for CALR and CD47 expression over time using flow cytometry. Flow cytometry co-culture and fluorescent microscopy assays were employed to evaluate phagocytosis under various treatment conditions. Results: ALK inhibitors increased CALR expression in both TKIs-sensitive and off-target resistant ALK+ cancer cells. Prolonged TKIs exposure also led to CD47 upregulation. The combination of ALK inhibitors and anti-CD47 mAb significantly enhanced phagocytosis compared to anti-CD47 alone, as confirmed by flow cytometry and fluorescent microscopy. Conclusions: Anti-CD47 mAb can quench DEMs while exposing pro-phagocytic signals, promoting tumor cell phagocytosis. ALK inhibitors induced immunogenic cell damage by upregulating CALR in both sensitive and off-target resistant tumors. Continuous TKIs exposure in off-target resistant settings also resulted in the upregulation of CD47 over time. Combining TKIs with a CD47 blockade may offer therapeutic benefits in ALK+ cancers, especially in overcoming off-target resistance where TKIs alone are less effective. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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16 pages, 3709 KiB  
Article
Polymeric Nanoparticles Potentiate the Anticancer Activity of Novel PI3Kα Inhibitors Against Triple-Negative Breast Cancer Cells
by Suhair Sunoqrot, Samah Abusulieh and Dima Sabbah
Biomedicines 2024, 12(12), 2676; https://doi.org/10.3390/biomedicines12122676 - 24 Nov 2024
Cited by 1 | Viewed by 1005
Abstract
Background: Dysregulation in phosphoinositide-3-kinase alpha (PI3Kα) signaling is implicated in the development of various cancers, including triple-negative breast cancer (TNBC). We have previously synthesized a series of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides as targeted inhibitors against PI3Kα. Herein, two drug candidates, R7 and R11, were selected [...] Read more.
Background: Dysregulation in phosphoinositide-3-kinase alpha (PI3Kα) signaling is implicated in the development of various cancers, including triple-negative breast cancer (TNBC). We have previously synthesized a series of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides as targeted inhibitors against PI3Kα. Herein, two drug candidates, R7 and R11, were selected to be further investigated as a nanoparticle (NP) formulation against TNBC. Methods: R7 and R11 were entrapped in D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) polymeric NPs by nanoprecipitation. Following their physicochemical characterization, the anticancer activity of the compounds and their NP formulations was evaluated in the TNBC cell line MDA-MB-231 by conducting viability, uptake, and apoptosis assays, as well as penetration assays in a multicellular tumor spheroid model. Results: The NPs exhibited a particle size of 100–200 nm, excellent drug loading efficiencies, and sustained release under physiologic conditions. Viability assays revealed superior potency for the NP formulations, with IC50 values of 20 µM and 30 µM for R7- and R11-loaded NPs, respectively, compared to the free compounds, which exhibited IC50 values of 280 µM and 290 µM for R7 and R11, respectively. These results were attributed to the inherent antiproliferative activity of TPGS, as evidenced by the cytotoxicity of the drug-free NPs, as well as the enhanced cellular uptake enabled by the NP vehicle, as demonstrated by fluorescence microscopy imaging and flow cytometry measurements. Further investigations showed that the NPs promoted apoptosis via a mitochondrial-dependent pathway that involved the activation of proapoptotic caspases. Moreover, the NP formulations enhanced the penetration ability of the free compounds in multicellular tumor spheroids, causing a time- and concentration-dependent disruption of the spheroids. Conclusions: Our findings highlight the important role nanotechnology can play in improving the biopharmaceutical properties of new drug candidates and facilitating their in vivo translation. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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Review

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19 pages, 809 KiB  
Review
Overcoming Cancer Resistance: Strategies and Modalities for Effective Treatment
by Mahesh Koirala and Mario DiPaola
Biomedicines 2024, 12(8), 1801; https://doi.org/10.3390/biomedicines12081801 - 8 Aug 2024
Cited by 8 | Viewed by 4714
Abstract
Resistance to cancer drugs is a complex phenomenon that poses a significant challenge in the treatment of various malignancies. This review comprehensively explores cancer resistance mechanisms and discusses emerging strategies and modalities to overcome this obstacle. Many factors contribute to cancer resistance, including [...] Read more.
Resistance to cancer drugs is a complex phenomenon that poses a significant challenge in the treatment of various malignancies. This review comprehensively explores cancer resistance mechanisms and discusses emerging strategies and modalities to overcome this obstacle. Many factors contribute to cancer resistance, including genetic mutations, activation of alternative signaling pathways, and alterations in the tumor microenvironment. Innovative approaches, such as targeted protein degradation, immunotherapy combinations, precision medicine, and novel drug delivery systems, hold promise for improving treatment outcomes. Understanding the intricacies of cancer resistance and leveraging innovative modalities are essential for advancing cancer therapy. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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Other

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15 pages, 1431 KiB  
Systematic Review
Clinical Outcomes and Molecular Predictors of Pembrolizumab (Keytruda) as a PD-1 Immune Checkpoint Inhibitor in Advanced and Metastatic Cervical Cancer: A Systematic Review and Meta-Analysis
by Lavinia Balan, Anca Maria Cimpean, Prashant Sunil Nandarge, Bogdan Sorop, Catalin Balan, Madalina Alexandra Balica, Felix Bratosin, Simona Brasoveanu, Madalina Boruga and Laurentiu Pirtea
Biomedicines 2024, 12(5), 1109; https://doi.org/10.3390/biomedicines12051109 - 16 May 2024
Cited by 4 | Viewed by 3210
Abstract
This systematic review evaluates the clinical outcomes and molecular predictors of response to pembrolizumab in patients with advanced and metastatic cervical cancer. We adhered to the PRISMA guidelines for systematic reviews, conducting a database search in PubMed, Scopus, and Embase. The eligibility criteria [...] Read more.
This systematic review evaluates the clinical outcomes and molecular predictors of response to pembrolizumab in patients with advanced and metastatic cervical cancer. We adhered to the PRISMA guidelines for systematic reviews, conducting a database search in PubMed, Scopus, and Embase. The eligibility criteria centered on clinical outcomes, including the overall survival (OS), progression-free survival (PFS), and immune-related biomarkers post-pembrolizumab therapy. We included both prospective and retrospective studies that detailed clinical outcomes and molecular characteristics predictive of therapeutic response. Our search yielded six studies involving 846 patients treated with pembrolizumab from 2017 to 2022. The meta-analysis of these studies showed that pembrolizumab, used as monotherapy or in combination with chemotherapy, extended the OS by a weighted median of 10.35 months and the PFS by 8.50 months. The treatment demonstrated a pooled objective response rate (ORR) of 22.39%, although the I2 test result of 67.49% showed a high heterogeneity among the studies. Notably, patients with high PD-L1 expression (CPS ≥ 10) experienced improved outcomes in terms of the PFS and OS. The most common complications were fatigue, diarrhea, and immune-related adverse events. Pembrolizumab significantly enhances clinical outcomes in metastatic cervical cancer, particularly among patients with high PD-L1 expression. The drug maintains a good safety profile, reinforcing its treatment potential for patients with advanced and metastatic cervical cancer. Future studies should explore long-term effects and strategies to integrate pembrolizumab optimally into current treatment regimens, aiming to maximize patient benefits and effectively manage side effects. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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