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Drugs Targeting Cancer Signaling Pathways: Dissecting Mechanisms to Unlock New Therapeutic Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 October 2026 | Viewed by 3921

Special Issue Editor

Dr. Souleymane Abdoul-Azize

E-Mail Website
Guest Editor
Brown Center for Immunotherapy, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Interests: childhood cancers; blood cancers; ion channels; calcium signaling; therapeutic resistance; signaling transduction; drug mechanisms of action

Special Issue Information

Dear Colleagues,

Cancer cells continuously evolve survival strategies, enabling resistance to therapeutic drugs. This resistance remains a major challenge, limiting the efficacy of existing treatments. Oncogenic signaling pathways orchestrate various cellular and molecular processes, including survival, proliferation, apoptosis, metabolism, epigenetic modifications, and tumor suppressor regulation. Identifying and targeting key signaling pathways with optimal anticancer activity and minimal toxicity has emerged as a promising approach to overcoming this hurdle.

This Special Issue will cover in vitro and in vivo studies exploring advances in deciphering cancer signaling mechanisms underlying resistance to therapies and the role of novel drugs in modulating these signaling pathways to accelerate the discovery of new therapeutic targets.

In this Special Issue, original research articles and reviews on solid and hematological malignancies are welcome.

Dr. Souleymane Abdoul-Azize
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 250 words) can be sent to the Editorial Office for assessment.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • small-molecule drugs
  • signal transduction
  • therapeutic targets
  • therapeutic resistance
  • oncogenic signaling
  • novel biomarkers
  • cancer therapy
  • cancer signaling pathways
  • immunotherapy

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Published Papers (3 papers)

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Research

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17 pages, 1616 KB  
Article
Enhancing Chemotherapeutic Efficacy in Lung Cancer Cells Through Synergistic Targeting of the PI3K/AKT Pathway with Small Molecule Inhibitors
by Maria Michael, Maria Christou, Iason Kanakas and Christiana M. Neophytou
Int. J. Mol. Sci. 2025, 26(17), 8378; https://doi.org/10.3390/ijms26178378 - 28 Aug 2025
Viewed by 1688
Abstract
Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality, with resistance to chemotherapy representing a major therapeutic challenge. In this study, we investigated the effects of conventional chemotherapeutics, Cisplatin and 5-fluorouracil (5-FU), in combination with small molecule inhibitors [...] Read more.
Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality, with resistance to chemotherapy representing a major therapeutic challenge. In this study, we investigated the effects of conventional chemotherapeutics, Cisplatin and 5-fluorouracil (5-FU), in combination with small molecule inhibitors (SMIs) targeting the PI3K/AKT signaling pathway, on NSCLC cell viability. Two NSCLC cell lines, H460 (large cell lung carcinoma) and A549 (adenocarcinoma), both characterized by constitutive activation of PI3K/AKT signaling, were evaluated. A normal human lung fibroblast cell line, MRC-5, was used as a non-cancer control to assess selectivity and exclude cytotoxic effects. Dose–response analyses were performed to determine the optimal concentrations of Cisplatin, 5-FU, the AKT inhibitor MK2206, and the PI3K inhibitor BKM120, both as monotherapies and in combination treatments. We identified a synergistic combination of 5-FU and BKM120 that significantly reduced viability and induced apoptosis in NSCLC cells while sparing MRC-5 cells. Mechanistic studies revealed that apoptosis induction was mediated through the apoptotic pathway regulated by the Bcl-2 family and activation of caspase-3 and caspase-6. These findings highlight the therapeutic potential of combining PI3K/AKT inhibitors with conventional chemotherapy to overcome resistance mechanisms in NSCLC. Full article
(This article belongs to the Special Issue Drugs Targeting Cancer Signaling Pathways: Dissecting Mechanisms to Unlock New Therapeutic Targets)
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12 pages, 2091 KB  
Article
Opposing Calcium-Dependent Effects of GsMTx4 in Acute Lymphoblastic Leukemia: In Vitro Proliferation vs. In Vivo Survival Advantage
by Souleymane Abdoul-Azize, Rachid Zoubairi and Olivier Boyer
Int. J. Mol. Sci. 2025, 26(10), 4822; https://doi.org/10.3390/ijms26104822 - 18 May 2025
Viewed by 1170
Abstract
Mechanogated (MG) ion channels play a crucial role in mechano-transduction and immune cell regulation, yet their impact on blood cancers, particularly acute lymphoblastic leukemia (ALL), remains poorly understood. This study investigates the pharmacological effects of GsMTx4, an MG channel inhibitor, in human ALL [...] Read more.
Mechanogated (MG) ion channels play a crucial role in mechano-transduction and immune cell regulation, yet their impact on blood cancers, particularly acute lymphoblastic leukemia (ALL), remains poorly understood. This study investigates the pharmacological effects of GsMTx4, an MG channel inhibitor, in human ALL cells both in vitro and in vivo. Unexpectedly, we found that GsMTx4 remarkably increased basal calcium (Ca2+) levels in ALL cells through constitutive Ca2+ entry and enhanced store-operated Ca2⁺ influx upon thapsigargin stimulation. This increase in basal Ca2+ signaling promoted ALL cell viability and proliferation in vitro. Notably, chelating intracellular Ca2+ with BAPTA-AM reduces GsMTx4-mediated leukemia cell viability and proliferation. However, in vivo, GsMTx4 decreases cytosolic Ca2+ levels in Nalm-6 GFP⁺ cells isolated from mouse blood, effectively countering leukemia progression and significantly extending survival in NSG mice transplanted with leukemia cells (median survival: GsMTx4 vs. control, 37.5 days vs. 29 days, p = 0.0414). Our results highlight the different properties of GsMTx4 activity in in vitro and in vivo models. They also emphasize that Ca2+ signaling is a key vulnerability in leukemia, where its precise modulation dictates disease progression. Thus, targeting Ca2+ channels could offer a novel therapeutic strategy for leukemia by exploiting Ca2+ homeostasis. Full article
(This article belongs to the Special Issue Drugs Targeting Cancer Signaling Pathways: Dissecting Mechanisms to Unlock New Therapeutic Targets)
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Review

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19 pages, 680 KB  
Review
Dipeptide Transport Systems at the Interface of Peptide Metabolism and Drug Delivery in Cancer
by Kyung-Hee Kim and Byong Chul Yoo
Int. J. Mol. Sci. 2026, 27(9), 3728; https://doi.org/10.3390/ijms27093728 - 22 Apr 2026
Viewed by 160
Abstract
Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide [...] Read more.
Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide transporter 2 (PEPT2/SLC15A2), mediate the proton-coupled uptake of dipeptides, tripeptides, and structurally related compounds across cellular membranes. While these transporters have been extensively studied in the context of intestinal peptide absorption and drug delivery, their potential roles in cancer biology remain incompletely understood. Tumor microenvironments are characterized by extensive proteolysis and dynamic metabolic remodeling, processes that can generate diverse peptide fragments derived from extracellular matrix proteins and intracellular protein turnover. These peptides may accumulate locally and potentially serve as substrates for cellular peptide transport systems. Once internalized through peptide transporters, dipeptides are typically hydrolyzed into free amino acids that can support biosynthetic pathways, energy metabolism, and cellular growth. In addition to their potential metabolic roles, certain endogenous dipeptides have also been reported to influence cellular signaling pathways and redox homeostasis. The broad substrate specificity of peptide transporters has also attracted significant interest in pharmacology because numerous clinically used drugs exploit these transport systems for efficient cellular uptake. This property raises the possibility that peptide transporters may be utilized for transporter-mediated drug delivery strategies, including the development of peptide-modified prodrugs or dipeptide–drug conjugates. In this review, we summarize the molecular characteristics and physiological functions of dipeptide transport systems with a particular focus on the SLC15 transporter family. We then discuss emerging evidence linking peptide transporters to tumor metabolism and the tumor microenvironment. Finally, we highlight current progress and future perspectives in exploiting peptide transport systems for transporter-mediated drug delivery and therapeutic targeting in cancer. Full article
(This article belongs to the Special Issue Drugs Targeting Cancer Signaling Pathways: Dissecting Mechanisms to Unlock New Therapeutic Targets)
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