Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance.

Background

Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models.

Methods

A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated

Results

The nature of TTFields-drug interaction was dependent on the drug's underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.

Conclusion

By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and

Informations de copyright

Copyright © 2024 Berckmans, Ene, Ben-Meir, Martinez-Conde, Wouters, Van den Ende, Van Mechelen, Monin, Frechtel-Gerzi, Gabay, Dor-On, Haber, Weinberg, Vergote, Giladi, Coosemans and Palti.

Déclaration de conflit d'intérêts

IV declares consultancy honoraria from Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Elsevier, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, Molecular Partners, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Regeneron, Seagen, Sotio, Verastem Oncology, Zentalis. AC is a contracted researcher for Oncoinvent AS and Novocure and a consultant for Sotio a.s., Epics Therapeutics SA and Molecular Partners. RW is employed by Oncoinvent AS. HE, KB, AM, RM, RF, HG, ED, AH, MG, and UW are employees of Novocure and hold company stocks. MG and UW hold Novocure IP. YP is the founder of Novocure, holding company stock and IP. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Novocure Ltd. The funder had the following involvement in the study: the authors affiliated with Novocure Ltd conducted part of the study.