Abstract 2273: Meta-analysis of cancer cell lines based on responses to Tumor Treating Fields (TTFields)
Authors: Shahaf Gitit Lavy , Giladi Moshe , Schneiderman Rosa S. , Urman Noa , Gotlieb Karnit , Zeevi Einav , Porat Yaara , Munster Mijal , Kinzel Adrian , Weinberg Uri , Kirson Eilon D. , Palti Yoram 
Published: August 2018

Objective: Tumor Treating Fields (TTFields) therapy is an approved modality for the treatment of glioblastoma. These alternating electric fields were shown to exert an inhibitory effect in numerous cancer cell lines with some variability in the responses of different cell lines. The goal of the present study is to compare characteristics of cell lines based on their response pattern to TTFields.

Methods: Forty different human cancerous cell lines were treated for 72 hours with TTFields at respective cell-specific optimal frequency with the same nominal intensity (1.7 V/cm). Cell survival and clonogenicity were determined. Functional analysis of differentially expressed genes and mutations associated with response to TTFields was performed based on the Cancer Cell Line Encyclopedia (CCLE) database. Sensitivity to TTFields was compared with pharmacologic profiling (CCLE).

Results: TTFields application demonstrated varying degrees of cytotoxic effects in all cell lines tested. The inhibitory response to TTFields was found to be distributed around an average of 50% with cytotoxic effects ranging between 14% and 86% reductions in cell counts, and a clonogenic effect ranging between no effect and 88% reduction in the number of colonies. In line with TTFields' anti-mitotic properties, a correlation between treatment efficacy and cell doubling time was demonstrated. However, few cell lines demonstrated enhanced treatment efficacy despite long doubling time, suggesting other factors may also be involved in the response to treatment. Pharmacologic profiling based on IC50 values revealed increased sensitivity to lapatinib, PHA-665752 and PLX-4720 within the group of cell lines that were less sensitive to TTFields. Functional analyses of cell line gene expression and mutation data revealed enriched pathways related to DNA damage repair response such as the BRCA1 repair pathway, which validate previous data obtained using different methodologies. Other pathways that were found to be associated with sensitivity to TTFields include cell migration, hypoxia signaling, and oxidative stress.

Conclusion: This multiparameter, large-scale comparison of cancer cell line responses demonstrates the broad effectiveness of TTFields in various cell lines and defines the optimal frequency to be applied for each cell line. The data presented in this work suggest that beside anti-mitotic properties, TTFields may have effects on other cellular pathways. The pharmacologic profiling may offer a rational for combining specific agents with TTFields in cells that are less sensitive to the electric fields.

Citation Format: Gitit Lavy Shahaf, Moshe Giladi, Rosa S. Schneiderman, Noa Urman, Karnit Gotlieb, Einav Zeevi, Yaara Porat, Mijal Munster, Adrian Kinzel, Uri Weinberg, Eilon D. Kirson, Yoram Palti. Meta-analysis of cancer cell lines based on responses to Tumor Treating Fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2273.