The editorial also emphasizes that the proposed approaches are research directions, many of which remain preclinical or computational, and that translation into durable clinical benefit will require further mechanistic work, biomarker development and validation. A recurring theme is the ability of tumour cells to adapt to therapeutic pressure through states that are not fixed by permanent genetic changes. The editorial describes drug-tolerant persister cells as transient and reversible phenotypes that allow cancer cells to survive treatment-induced stress without permanent genetic alterations.

These tolerance states may serve as an intermediate step toward stable acquired resistance. The collection therefore treats resistance as a process involving both cellular adaptation and evolutionary change, while presenting the relationship between non-genetic tolerance and later stable resistance as a concept supported by cited research rather than as a result newly established by the editorial itself. One contribution focuses on the epigenetic regulator EZH2 in the context of doxorubicin resistance in breast cancer.

The article summarized by the editorial reports that pharmacological inhibition of EZH2 enhanced DNA damage and promoted metabolic vulnerability in resistant cancer cells, thereby restoring therapeutic sensitivity in the experimental setting. The result suggests that an epigenetic intervention can influence several cellular processes at once, linking chromatin regulation with DNA damage and metabolism. The evidence described here comes from a preclinical cancer-cell study, not from a demonstration that EZH2 blockade improves outcomes in patients with resistant breast cancer.

The editorial also notes clinical and regulatory challenges associated with the EZH2 inhibitor tazemetostat, illustrating the difficulty of translating an apparently attractive biological strategy into clinical benefit. Resistance to therapies directed at DNA-damage response pathways is addressed through a study of eprenetapopt combined with carboplatin in high-grade ovarian and triple-negative breast cancer cell lines with acquired resistance to olaparib. Eprenetapopt is described as a small molecule that can restore wild-type-like p53 function in TP53-mutant cells and promote ferroptosis-associated cellular responses.

The reported synergistic activity in these olaparib-resistant models supports the rationale for testing combinations that exploit vulnerabilities remaining in DNA-repair pathways. It does not establish that the combination is effective in people, that it can overcome resistance in a clinical setting, or that the laboratory result predicts a safe and effective treatment schedule. The contribution instead provides a preclinical example of how resistance mechanisms can guide experimental combination design.

The collection also examines computational approaches to treatment selection. A contribution on personalized Boolean network dynamic profiling and machine learning addresses the identification of combinatorial treatments for prostate cancer. The editorial describes these systems-biology and machine-learning approaches as tools for analyzing patient-specific therapeutic vulnerabilities and optimizing combinations of treatments.

This work complements experimental studies by providing a framework for relating molecular states to possible treatment responses. The proposed potential for more precise treatment strategies remains a research aim. The editorial does not provide evidence that a machine-learning-selected combination has been tested in a clinical trial, that it is superior to standard treatment, or that computational optimization has already resolved treatment resistance in patients.

Signalling controlled by non-coding RNA and oncogenic pathways provides another possible source of resistance. An article on gastric cancer identifies FAM66C as a contributor to proliferation and chemoresistance through regulation of nuclear YAP signalling. The reported mechanism links FAM66C activity with phosphorylation of YAP and places the long non-coding RNA within a molecular circuit that may govern treatment responsiveness.

This finding broadens the set of biological pathways considered relevant to refractory gastric cancer and identifies lncRNA-associated pathways as possible subjects for biomarker and drug research. As with the other experimental contributions described in the editorial, the therapeutic implication is not a clinical recommendation. The evidence presented supports a mechanistic association and a rationale for further investigation, not proof of benefit in patients.

Resistance in breast cancer is also considered through a review of sequential antibody-drug conjugate therapy. The contribution examines an “ADC-after-ADC” paradigm in which resistance following one antibody-drug conjugate is relevant to the use of another. Its stated focus includes cross-resistance, the order in which such treatments are used and the importance of patient selection.

The review synthesizes these issues rather than reporting a new comparative clinical trial, and its findings concern why sequential treatment may not always produce the expected benefit and which questions future studies must address. The editorial presents insight into cross-resistance and sequencing as important for the design of future studies and for strategies intended to delay resistance, but it does not establish a specific treatment sequence as preferable for individual patients. Preclinical work on a pterocarpan compound adds another route to the collection.

A proteomic study of the pterocarpan (+)-PTC in metastatic castration-resistant prostate cancer reported effects on proteins associated with cytoskeletal organization and apoptosis-related signalling. The authors interpreted these changes as possible mechanisms underlying the compound’s anti-tumour activity. This result supports further investigation of bioactive natural products as potential sources of new agents for advanced prostate cancer.

The evidence described in the editorial is based on laboratory analysis and does not demonstrate safety, clinical efficacy, a usable dose or comparative effectiveness against established treatments in people with metastatic castration-resistant prostate cancer. Pathological assessment and the tumour microenvironment broaden the scope of resistance research. A clinicopathological and immunohistochemical analysis of poorly differentiated squamous cell carcinoma examined molecular and pathological features associated with disease progression and quality of life.

The editorial interprets this work as demonstrating the value of detailed tissue assessment for treatment decisions and for identifying prognostic biomarkers that may support patient stratification. A separate review examines thrombospondin-2 and emphasizes its context-dependent and sometimes paradoxical pro-tumourigenic role in stromal signalling, moving beyond an angiogenic focus. Together, these contributions show why resistant disease cannot be understood solely through tumour-cell-autonomous changes.

Across the eight contributions, the editorial’s central message is that overcoming cancer drug resistance will require a combination of mechanistically informed combination therapies, longitudinal tumour characterization and emerging analytical technologies such as multi-omics and artificial intelligence. The proposed objective is to identify actionable vulnerabilities as tumours evolve under treatment. The evidence assembled includes cell-line experiments, computational models, proteomic analysis, clinical-pathological research and literature reviews, so it is not a unified clinical demonstration that the proposed strategies improve survival.

Rather, it maps a set of complementary research directions: reversible drug-tolerant states, epigenetic and metabolic adaptations, persistent DNA-repair vulnerabilities, non-coding RNA signalling, cross-resistance among antibody-drug conjugates, natural-product mechanisms, prognostic stratification and microenvironmental signalling. The editorial ultimately frames resistance not as an inevitable endpoint of cancer therapy, but as an adaptive process that can reveal new targets and guide the development of better-tested pharmacological strategies.

Subject of Research: Mechanisms of cancer drug resistance and emerging pharmacological strategies

Article Title: Editorial: Mechanisms of drug resistance in cancer: overcoming barriers with novel pharmacological strategies

Article References: Kar, P., Colangelo, D., Kumar, M. S., & Guncheva, M. (2026). Editorial: Mechanisms of drug resistance in cancer: overcoming barriers with novel pharmacological strategies. Frontiers in Pharmacology, 17, Article 1996202. https://doi.org/10.3389/fphar.2026.1996202

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1996202

Keywords: cancer drug resistance, precision oncology, targeted therapy, drug-tolerant persister cells, DNA damage response, antibody-drug conjugates, tumour microenvironment, machine learning, epigenetic therapy, combination treatment, Editorial, Mechanisms