Abstract 380: Tumor treating fields enhance cellular drug uptake in mesothelioma cell lines
Authors: Lupi Monica , Amodeo Rosy , Morosi Lavinia , Mannarino Laura , Paracchini Lara , Marchini Sergio , Grosso Federica , Libener Roberta , Ceresoli Giovanni L. , D'Incalci Maurizio 
Published: June 2022

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a 5-year survival rate of less than 10% and it remains a cancer lacking effective therapy options when tumors progress. The development of novel drug regimens for MPM treatment have been limited during the last two decades, with the exception of combinations including immune checkpoint inhibitors. In 2019, Tumor Treating Fields (TTFields) in combination with pemetrexed plus platinum-based chemotherapy were approved by the FDA for the first-line treatment of unresectable, locally advanced or metastatic, MPM. However, the mechanism of action of TTFields and their interaction with chemotherapeutic agents are not fully elucidated yet, thus a better knowledge may contribute to the design of more effective clinical trials for MPM patients. A panel of primary MPM cells was isolated from pleural effusion and/or lavages of patients’ thoracic cavity, before administration of therapeutic treatment, obtaining cell lines from the 3 subtypes of MPM. Epithelioid and sarcomatoid subtypes revealed different sensitivities to TTFields, with a stronger impact of the treatment on cell proliferation in the epithelioid subtype. This was associated with a higher modulation of transcription at different times of TTFields exposure, as demonstrated by RNA-seq analysis. Some of the genes modulated by the treatment encode membrane transport proteins, especially of the solute carrier family (SLC), in both sarcomatoid and epithelioid cells. This suggested a possible role of TTFields in cellular drug uptake and efflux. To test this hypothesis two cell lines, the sarcomatoid CD60 and the epithelioid CD473, have been treated with 150 kHz TTFields in combination with doxorubicin (DXR) following different schedules of treatment and the intracellular drug concentrations were assessed by HPLC measurements. TTFields exposure increased cellular uptake of DXR in both MPM models, but the effect was higher in CD473 epithelioid cells. After 24h of treatment with 1 µM DXR the amount of intracellular drug in sarcomatoid cells exposed to TTFields was almost twice that of the samples treated with DXR alone, while in epithelioid cells intracellular DXR concentration was almost four times higher than that found in TTFields untreated samples. This behavior might be ascribed to a different modulation of the gene coding for P-glycoprotein (ABCB1), which was markedly downregulated by TTFields treatment in epithelioid cells only. Similar experiments are in progress to test the impact of TTFields on cellular drug uptake in different combination schedules with other anticancer compounds. These data suggest that TTFields may increase the efficacy of drug treatments by enhancing the intracellular drug concentration and their possible confirmation by further experiments may represent an important rationale for the design of novel MPM therapies.
Citation Format: Monica Lupi, Rosy Amodeo, Lavinia Morosi, Laura Mannarino, Lara Paracchini, Sergio Marchini, Federica Grosso, Roberta Libener, Giovanni L. Ceresoli, Maurizio D'Incalci. Tumor treating fields enhance cellular drug uptake in mesothelioma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 380.