2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.03F.04 Treatment of Non-Small Cell Lung Carcinoma (NSCLC) Cells with Tumor Treating Fields (TTFields) And DNA-Dependent Protein Kinase (PK) Inhibitors

EP.03F.04 Treatment of Non-Small Cell Lung Carcinoma (NSCLC) Cells with Tumor Treating Fields (TTFields) And DNA-Dependent Protein Kinase (PK) Inhibitors

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The study presented by researchers from Novocure Ltd. investigates the effects of combining Tumor Treating Fields (TTFields) with DNA-dependent protein kinase inhibitors (DNA-PKis), namely nedisertib and CC-115, on non-small cell lung carcinoma (NSCLC) cells. TTFields, which are non-invasive electric fields, disrupt key cellular processes that sustain cancer cell viability and tumor growth, particularly by compromising DNA repair mechanisms such as the homologous recombination (HR) pathway. In combination with DNA-PKis—agents that target the non-homologous end-joining (NHEJ) pathway responsible for repairing double-strand breaks (DSBs)—the treatment may increase DNA damage to lethal levels in cancer cells.<br /><br />In the study, two NSCLC cell lines, A549 and H1299, were tested. TTFields, applied at a specific intensity and frequency, were paired with various concentrations of the DNA-PK inhibitors nedisertib and CC-115 over 72 hours. The effectiveness of these combinations was assessed using cell proliferation assays, clonogenic survival analyses, apoptosis detection, cell cycle distribution evaluation, and measurement of DNA damage markers. The results showed that TTFields synergistically enhance the cytotoxic effects of the inhibitors on the A549 cells by facilitating G1 cell cycle arrest and increasing DNA damage, notably through decreased expression of BRCA2, a key protein in DNA repair.<br /><br />Additionally, the interplay between TTFields and nedisertib was stronger in A549 cells compared to H1299 cells, attributed to certain genetic variations in the latter. CC-115, with its dual action against DNA-PK and mTOR pathways, exhibited a comparably stronger effect in combination with TTFields. These findings suggest a promising therapeutic strategy that may also sensitize cancer cells to radiation therapy, which similarly causes DSBs, offering potential for enhanced treatment outcomes in NSCLC. Future studies are planned to further explore these synergistic effects.

Asset Subtitle

Yiftah Barsheshet

Meta Tag

Speaker Yiftah Barsheshet

Topic Tumor Biology – Translational Biology

Keywords

Tumor Treating Fields

DNA-PK inhibitors

non-small cell lung carcinoma

NSCLC

nedisertib

CC-115

DNA damage

cell cycle arrest

BRCA2

synergistic effects