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Cancers
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Cancer Cell Vulnerabilities on Pathways Regulating the Cell Cycle
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Cancer Cell Vulnerabilities on Pathways Regulating the Cell Cycle

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

Deadline for manuscript submissions: 31 December 2026 | Viewed by 3677

Editor

Prof. Dr. Hiroaki Kiyokawa

E-Mail Website
Guest Editor
Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA
Interests: cancer biology; ubiquitination; phosphorylation; cell cycle; oncogenic signaling; mouse models; drug targets; drug development; proteomics; breast cancer; human papillomavirus (HPV)-associated cancers

Special Issue Information

Dear Colleagues,

Dysregulated cell cycle progression, which leads to multiple cancer hallmarks, could result from not only genetic or epigenetic alterations in cell cycle-regulatory genes (e.g., cyclins, CDKs, and CKIs), but also perturbation of numerous signaling pathways that converge at the cell cycle machinery. Successful development of therapies targeting cell cycle machinery such as CDK4/6 inhibitors, together with therapies targeting the upstream convergent signaling pathways including EGFR, HER2, RAF, MEK, PI3K, and AKT, opened a new era of precision medicine in cancer therapeutics. While CDK4/6 inhibitors have become essential agents in clinics, insights into cancer cell vulnerabilities associated with various oncogenic mutations remain limited. Questions have yet to be addressed, e.g., how to address cancer type-specific cell cycle dysregulation by targeting individual cell cycle components including CDKs, aurora kinases, and polo-like kinases; how to overcome resistance to cell cycle-targeting drugs; and what would be rationalized choices of combinational therapies targeting cell cycle machinery and the upstream convergent oncogenic pathways.

For this Special Issue, we invite original research articles as well as review articles that deal with the linkage of cancer-driving signaling pathways and cell cycle dysfunction, with particular focus on implications for strategic precision medicine.

Prof. Dr. Hiroaki Kiyokawa
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 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-anonymized 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

  • cell cycle
  • signaling pathway
  • precision medicine

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Published Papers (3 papers)

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Research

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23 pages, 6698 KB  
Article
Chronic IFN-γ Exposure Induces Divergent Adaptive Programs in Glioblastoma Subtypes
by Elnaz Rahbarlayegh, Natsuko Nomura, Tiffany M. Juarez, Pranav R. Kesari and Santosh Kesari
Cancers 2026, 18(10), 1552; https://doi.org/10.3390/cancers18101552 - 11 May 2026
Viewed by 628
Abstract
Background: Immunotherapy has transformed cancer treatment by enhancing cytotoxic T-cell activity and interferon-γ (IFN-γ)-mediated tumor clearance. However, glioblastoma (GBM) remains largely refractory to these approaches, reflecting a profoundly immunosuppressive and myeloid-dominant tumor microenvironment. IFN-γ is central to antitumor immunity, yet chronic exposure can [...] Read more.
Background: Immunotherapy has transformed cancer treatment by enhancing cytotoxic T-cell activity and interferon-γ (IFN-γ)-mediated tumor clearance. However, glioblastoma (GBM) remains largely refractory to these approaches, reflecting a profoundly immunosuppressive and myeloid-dominant tumor microenvironment. IFN-γ is central to antitumor immunity, yet chronic exposure can paradoxically promote adaptive resistance. How GBM cells respond to sustained IFN-γ signaling, and whether these responses differ across tumor states, remains poorly understood. Methods: To address this, we modeled chronic IFN-γ exposure in mesenchymal-like (U87) and proneural-like (U251) GBM cells over 28 days and performed integrated analyses of transcriptional, proteomic, and secretory responses. Results: While IFN-γ initially suppressed growth in both models, their long-term adaptations diverged. U87 cells developed a persistence-prone state characterized by progressive activation of PI3K–AKT signaling, whereas U251 cells exhibited sustained interferon signaling with persistent interferon-related DNA damage resistance signature (IRDS) expression and suppressed AKT activity. These transcriptional and signaling programs were incompletely reversible after cytokine withdrawal, indicating stable interferon conditioning. Analysis of TCGA glioblastoma datasets demonstrated that interferon-associated transcriptional programs are present across human tumors and are positively associated with PI3K–AKT pathway activity across molecular subtypes. Conclusions: Together, these findings reveal that chronic IFN-γ exposure drives distinct, lineage-dependent adaptive states in GBM, linking interferon signaling to divergent survival and immune-modulatory programs. While IFN-γ enhances immune activation, prolonged signaling may also promote tumor persistence. These results support therapeutic strategies that combine IFN-based approaches with interventions targeting adaptive survival pathways and immune reprogramming. Full article
(This article belongs to the Special Issue Cancer Cell Vulnerabilities on Pathways Regulating the Cell Cycle)
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Review

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21 pages, 1344 KB  
Review
Reframing RB Tumor Suppressor Dysfunction as a Therapeutic Vulnerability in Cancer
by Rada Malko, Harlan E. Shannon, Erika A. Dobrota, Keiko E. Kreklau, Lauren K. Stevens, Kyle W. Jackson, M. Reza Saadatzadeh, Pankita H. Pandya and Karen E. Pollok
Cancers 2026, 18(7), 1175; https://doi.org/10.3390/cancers18071175 - 7 Apr 2026
Viewed by 833
Abstract
The retinoblastoma (RB) protein was the first tumor suppressor discovered and has been extensively studied for its canonical role in cell-cycle regulation. However, RB has broader noncanonical roles in DNA damage repair, chromosomal stability, apoptosis control, lineage commitment, cell differentiation and broad transcriptional [...] Read more.
The retinoblastoma (RB) protein was the first tumor suppressor discovered and has been extensively studied for its canonical role in cell-cycle regulation. However, RB has broader noncanonical roles in DNA damage repair, chromosomal stability, apoptosis control, lineage commitment, cell differentiation and broad transcriptional regulation. Historically, RB inactivation has been associated with tumorigenesis, as well as resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), leading to its investigation as a potential predictive biomarker. However, clinical data have not demonstrated that RB function reliably predicts response to CDK4/6i consistently. These discrepancies highlight the need to reconsider RB’s role in therapeutic response, as RB loss can promote replication stress, induce chromosomal instability, and lead to transcriptional reprograming, potentially generating context-specific therapeutic vulnerabilities. In this review, we examine the multifaceted biology of RB and evaluate how its loss influences responses to chemotherapy and targeted therapies. We highlight emerging strategies that exploit RB-deficient states using rational monotherapy and combination approaches. Reframing RB dysfunction from a binary biomarker to a driver of exploitable cellular vulnerabilities may inform and expand precision oncology strategies for aggressive and treatment-resistant cancers. Full article
(This article belongs to the Special Issue Cancer Cell Vulnerabilities on Pathways Regulating the Cell Cycle)
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Other

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13 pages, 660 KB  
Opinion
Frontiers in Cell-Cycle-Targeting Therapies: Addressing the Heterogeneity of the Cancer Cell Cycle
by Ishaar P. Ganesan and Hiroaki Kiyokawa
Cancers 2026, 18(2), 329; https://doi.org/10.3390/cancers18020329 - 21 Jan 2026
Cited by 1 | Viewed by 1399
Abstract
The cell division cycle machinery has been regarded as a promising therapeutic target for several decades. One of the most prominent milestones in the approach to targeting the cancer cell cycle was the development and approval of CDK4/6 inhibitors such as palbociclib, ribociclib, [...] Read more.
The cell division cycle machinery has been regarded as a promising therapeutic target for several decades. One of the most prominent milestones in the approach to targeting the cancer cell cycle was the development and approval of CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib. These small-molecule therapeutics have exhibited remarkable anti-cancer efficacy and have become primary choices for treating steroid receptor-positive breast cancer at multiple stages. This epoch-making success of cell-cycle-targeting drugs was followed by the development of small molecules to target other cell cycle-regulatory proteins, such as CDK2, CDK1, WEE1 kinase, Aurora kinases, and polo-like kinases, while therapeutic strategies to overcome resistance to CDK4/6 inhibitors have been pursued. In this article, we focus on heterogeneous vulnerabilities of cancers as consequences of various genetic and epigenetic alterations in the cell cycle-regulatory network, and we discuss how next-generation cell-cycle-targeting drugs currently in the developmental pipeline could exploit these heterogeneous vulnerabilities in the cancer cell cycle. We hope to provide a forward-looking perspective on directions for therapeutic cell-cycle targeting in the advent of personalized precision medicine. Full article
(This article belongs to the Special Issue Cancer Cell Vulnerabilities on Pathways Regulating the Cell Cycle)
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