Tumor treating fields: a comprehensive overview of the underlying molecular mechanism

ABSTRACT

Introduction

As a novel treatment modality, tumor treating fields (TTFields) exert low-intensity, medium-frequency electric fields on tumor cells. TTFields’ effectiveness and safety have been demonstrated clinically and in the real world for treating glioblastoma, the most common and aggressive primary central nervous system tumor. TTFields therapy has also been approved for the management of malignant mesothelioma, and clinical trials are ongoing for NSCLC, gastric cancer, pancreatic cancer, and other solid tumors.

Areas covered

This article comprehensively reviews the currently described evidence of TTFields’ mechanism of action. TTFields’ most evident therapeutic effect is to induce cell death by disrupting mitosis. Moreover, evidence suggests at additional mechanistic complexity, such as delayed DNA repair and heightened DNA replication stress, reversible increase in cell membrane and blood–brain barrier permeability, induction of immune response, and so on.

Expert opinion

TTFields therapy has been arising as the fourth anti-tumor treatment besides surgery, radiotherapy, and antineoplastic agents in recent years. However, the precise molecular mechanisms underlying the effects of TTFields are not fully understood and some concepts remain controversial. An in-depth understanding of TTFields’ effects on tumor cell and tumor microenvironment would be crucial for informing research aimed at further optimizing TTFields’ efficacy and developing new combination therapies for clinical applications.

KEYWORDS:

• Antitumor activity
• combination therapy
• glioblastoma (GBM)
• molecular mechanism
• tumor treating fields (TTfields)

Article highlights

• Tumor treating fields (TTFields) is a novel, non-invasive and effective anti-tumor modality. The primary mechanism of action of TTFields is to stall tumor cell proliferation. TTFields’ interference with the cell cycle is multipronged and can induce different cell fates, including aberrant mitosis and cell death following cell division inhibition. Research into TTFields’ impact on mitosis and cell cycle provided clear evidence for TTFields’ anti-proliferative effects and suggests that combining TTFields with anti-mitotic drugs may achieve synergistic effects.

• Autophagy plays a dichotomous role in cancer by inhibiting tumor initiation but supporting tumor progression. Existing studies showed that TTFields could induce the upregulation of cell autophagy, but contradictory results have been reported as to whether autophagy is a pathway mediating TTFields’ cell death effect or a cellular resistance mechanism against it. Such discrepancy suggests that different cell lines respond to TTFields in different manners.

• In preclinical studies, TTFields showed the capacity to alter DNA repair, not only slowing down DNA damage repair kinetics but also inducing replication stress. Decreased replication fork speed was observed after TTFields treatment. This novel mechanism provides the rationale for combining TTFields with agents targeting the pathways of the DNA damage and repair process.

• Immunotherapy has been achieving tremendous development in the treatment of multiple malignant tumors. Interestingly, several studies found that TTFields may elicit antitumoral immunity. Further research demonstrated that the combination of TTFields and anti-PD1 therapy led to significantly decreased tumor volume compared with the monotherapy by either in an orthotopic Lewis lung carcinoma (LLC) mouse model. This promising result leads to an ongoing phase II clinical trial to explore the potential benefit of the combination therapy.

• In recent years, more and more valuable research findings have been revealed that can help investigator understand the complex effects TTFields exert on tumor cells. Other neoteric mechanisms of action of TTFields includes impact on cell migration and metastasis, reversible increase of cell membrane and blood-brain barrier permeability, and impairment of tumor aberrant glycolysis. Building on a deeper understanding of TTFields’ mechanism of action, ongoing and future research can hopefully expand the clinical application of TTFields in the form of combination therapy to treat a broader range of solid tumors.

Acknowledgments

The authors thank Professor Hai Jiang from State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, for the critical revision of the article for future direction, language modification and advising on the revision of the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [Research Grant 8167100079], Shanghai Municipal Science and Technology Major Project [No.2018SHZDZX01] and ZJLab.