Does coordinated targeting of metabolism and autophagy, modulated by microtubule dynamics, influence therapeutic vulnerability to eribulin in glioblastoma?

We thank Audet-Walsh and colleagues for their insightful commentary on our study addressing the repurposing of eribulin for glioblastoma (GBM) (1). The authors highlight several avenues for future investigation that will be carefully considered in upcoming projects. As they appropriately note, isocitrate dehydrogenase (IDH) mutations, frequent in gliomas, reprogram cellular metabolism by converting α-ketoglutarate (αKG) into the oncometabolite 2-hydroxyglutarate (2HG). This process leads to reduced αKG and nicotinamide adenine dinucleotide phosphate (NADPH) levels, induces mitochondrial metabolic stress, and limits the metabolic flexibility of tumor cells. In addition, 2HG inhibits αKG-dependent enzymes, including key epigenetic regulators, resulting in profound metabolic and epigenetic alterations (2). Selective inhibition of mutant IDH has emerged as a viable targeted therapy, with agents such as ivosidenib and vorasidenib promoting tumor differentiation, and demonstrating clinical efficacy and tolerability, culminating in the phase III INDIGO trial showing the superiority of vorasidenib in grade 2 IDH-mutant gliomas (3). The association of IDH inhibitors with eribulin has not yet been investigated. However, a potential therapeutic benefit can be hypothesized, as inhibition of mutant IDH reduces levels of 2HG, a constitutive activator of the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway (1), whose upregulation has been demonstrated to be associated with resistance to eribulin in glioma cells (4). The authors further suggest that eribulin alone may represent a promising therapeutic option for low-grade gliomas, in which resistance mechanisms associated with activation of the PI3K/AKT/mTOR pathway are less pronounced (1). We agree with this possibility, particularly considering that more pronounced antineoplastic effects of eribulin were observed in HOG cells, a model of oligodendroglioma, a low-grade glioma (4).

In high-grade glioma models, eribulin exhibited heterogeneous antineoplastic effects. As pointed out by the authors, eribulin’s reduced sensitivity has been observed in phosphatase and tensin homolog (PTEN)-mutated/PTEN-null cell lines such as U251MG (1), consistent with the idea that mutations leading to constitutive activation of the PI3K/AKT/mTOR pathway can blunt eribulin’s cytotoxic program (4). This relation could be particularly relevant in GBM, given the frequent upregulation of the PTEN/PI3K axis previously reported in these tumors (5). On this mechanistic basis, investigation of the association between eribulin and PI3K/AKT/mTOR pathway inhibitors appears promising for high-grade gliomas, since synergistic effects have already been proven in other types of solid tumors (6).

Another important issue that warrants further investigation concerns both the cause and the extent of mitochondrial dysfunction induced by eribulin. Mitochondria form a highly dynamic network whose homeostasis is essential for cellular metabolism, energy production, calcium handling, reactive oxygen species generation, and the regulation of programmed cell death. These processes critically depend on mitochondrial dynamics, including fusion, fission, biogenesis, mitophagy, and, importantly, intracellular mitochondrial trafficking (7). In this context, microtubules, the primary targets of eribulin, play a central role by serving as tracks for dynein- and kinesin-mediated mitochondrial transport, thereby ensuring the appropriate spatial distribution of mitochondria according to cellular energetic and metabolic demands. Disruption of this interaction compromises mitochondrial homeostasis and has been associated with metabolic adaptation and tumor progression, as mitochondrial redistribution supports cell survival, proliferation, and dissemination. Thus, the dependence of mitochondrial dynamics on microtubules underscores this axis as a fundamental component of cellular physiology and a potential therapeutic target in diseases such as cancer (8).

Eribulin is a microtubule-targeting agent with a unique mechanism of action. Unlike other drugs in this class that stabilize microtubules (e.g., taxanes) or promote their depolymerization (e.g., vinca alkaloids), eribulin converts microtubules into dysfunctional aggregates that are toxic to cells (9). This distinctive property may overload cellular recycling pathways such as autophagy and impair mitophagy, leading to the accumulation of dysfunctional mitochondria (8), a hypothesis that remains to be experimentally tested in future studies. Autophagy is a cellular process responsible for the degradation and recycling of intracellular components through autophagosomes and lysosomes. This mechanism maintains cellular homeostasis and can promote either cell survival or cell death, depending on the biological context. In breast cancer, eribulin induces robust activation of autophagy, characterized by increased microtubule-associated protein 1 light chain 3 beta, form II (LC3BII) levels and reduced sequestosome 1 (SQSTM1/p62) expression. This effect becomes synergistic when eribulin is combined with cisplatin, resulting in marked inhibition of tumor cell viability and clonogenic capacity. Notably, pharmacological inhibition of autophagy drastically attenuates the induced apoptosis, indicating that the observed cytotoxicity is functionally dependent on autophagy. Collectively, these findings position eribulin as an inducer of autophagy-dependent cell death and highlight an exploitable therapeutic vulnerability (10).

Given the urgent need to develop new therapies that improve both survival and quality of life for patients with GBM and considering the potential repositioning of eribulin for this malignancy, a deeper understanding of response biomarkers, resistance mechanisms, and pharmacological combinations capable of inducing synthetic lethality in tumor cells is of substantial value. In this regard, the commentary by Audet-Walsh and colleagues raises important points that extend the interpretation of our findings obtained in glioma cellular models and outlines promising new directions for investigation, ultimately helping to bridge the gap between bench research and clinical application (1).

In conclusion, we fully share the enthusiasm expressed by Audet-Walsh and colleagues and remain optimistic about the continued development of therapeutic options for GBM. We fully agree with the open question previously posed by the authors, “co-targeting cell metabolism and eribulin in GBM?”, and add “co-targeting autophagy and eribulin in GBM?”. We hope to contribute to further investigations aimed at addressing the knowledge gaps highlighted through this scientific exchange, as well as those identified herein.

Acknowledgments

The authors would like to thank Audet-Walsh and colleagues for initiating this important scientific dialogue and for opening a space for discussion aimed at advancing therapeutic strategies for glioblastoma.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article did not undergo external peer review.

Funding: This study was supported by the São Paulo Research Foundation (FAPESP) (grant 2023/12246-6). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), Finance Code 001.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0051/coif). J.A.M.N. serves as an unpaid editorial board member of Translational Cancer Research from August 2025 to September 2027. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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