Abstract 4883: Pan cancer transcriptomic response to tumor treating fields (TTFields)
Authors: Wainer-Katsir Kerem , Lavy-Shahaf Gitit , Fishman Hila , Ena Hila , Frechtel-Gerzi Roni , Martinez-Conde Antonia , Dor-On Eyal , Davidi Shiri , Jacobovitch Sara , Tzchori Itai , Porat Yaara , Ding Lianghao , Story Michael , Du Renfei , Kahlert Ulf , Mannarino Laura , Mirimao Federica , Lupi Monica , D’Incalci Maurizio , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: June 2023

Introduction: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is versatile with multiple mechanisms of action, including: anti-mitotic effects, downregulation of DNA double strand break repair, generation of replication stress, upregulation of autophagy, and induction of immunogenic cell death. In this research we were interested in identifying common responses to TTFields across cancer types. We addressed this by integrating whole transcriptome analyses of cancers from various origins.

Methods: Control and TTFields-treated samples examined included gastric, ovarian, pancreatic, non-small cell lung carcinoma, and glioblastoma cell lines, pleural mesothelioma patient-derived cell lines, and a hepatocellular carcinoma animal model. A list of differentially expressed genes (DEGs) was generated from transcriptomics analysis. Gene Set Enrichment Analysis (GSEA) was conducted with the MSigDB, and additional pathway databases. Significantly overlapping pathways were identified using ActivePathways package, and an enrichment map was created according to the number of datasets supporting each pathway.

Results: The response to TTFields showed a positive correlation of expression across different cell lines and indications, including in an animal model. Downregulation was seen in cell cycle related pathways - E2F targets, Myc targets, G2M checkpoint, and mitotic spindle - indicative of cell cycle arrest, which was mediated by increased expression of tumor suppressors. Several DNA repair pathways were downregulated, including nucleotide excision repair, base excision repair, and the Fanconi Anemia-BRCA pathway. Downregulation was also evident in nuclear envelope, DNA and RNA synthesis, metabolism of amino acids, translation, organelle organization, and splicing. Upregulation was observed in genes associated with the cytoskeleton, adhesion, extracellular proteins and transporters. In the majority of comparisons, an upregulation in the immune response was also observed.

Conclusions: Transcriptomic analysis of datasets from different tumor types revealed common expression patterns and pathways involved in the responses to TTFields. Some of the identified pathways corroborate previously described mechanisms, whereas some reveal new potential mechanisms that require further investigation.

Citation Format: Kerem Wainer-Katsir, Gitit Lavy-Shahaf, Hila Fishman, Hila Ena, Roni Frechtel-Gerzi, Antonia Martinez-Conde, Eyal Dor-On, Shiri Davidi, Sara Jacobovitch, Itai Tzchori, Yaara Porat, Lianghao Ding, Michael Story, Renfei Du, Ulf Kahlert, Laura Mannarino, Federica Mirimao, Monica Lupi, Maurizio D’Incalci, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Pan cancer transcriptomic response to tumor treating fields (TTFields). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4883.