Abstract 2344: BRAF inhibitor resistant thyroid cancer cells exhibit altered cellular energetics

Abstract

Abstract Thyroid cancer is the most commonly diagnosed endocrine malignancy. Although prognosis for patients is positive overall, dedifferentiated thyroid tumors and invasive thyroid tumors are difficult to treat. There is one FDA approved targeted therapy in use for in BRAF mutant, highly dedifferentiated anaplastic thyroid cancer, a combination of the BRAF inhibitor dabrafenib and the ERK inhibitor trametinib. While this treatment improves outcomes, resistance is of great concern. In other cancers driven by BRAF mutations, particularly melanoma, a known driver of BRAF inhibitor resistance is enhanced oxidative phosphorylation. We therefore investigated the energetics of thyroid cancer cells to determine whether metabolic changes can drive resistance in thyroid cancer. We have previously determined sensitivity to dabrafenib by area under the curve to classify cell lines as sensitive or resistant (Hicks HM et al, 2021). We used CUTC5 cells as our primary model of intrinsically sensitive cells and CUTC60 cells to model intrinsic resistance. We observed both cell lines had similar basal oxygen consumption rates (OCR), however dabrafenib treatment reduced this in the sensitive CUTC5 cells and did not in the resistant CUTC60 cells. Additionally, maximum OCR was reduced in the CUTC5 cells with as little as 10 nM dabrafenib. In a preliminary experiment, CUTC60 cells were co-treated with dabrafenib and rotenone, an inhibitor of the electron transport chain, and synergistic inhibition of proliferation was observed. We further investigated energetics in the dabrafenib sensitive cell line KTC1 and KTC1-VA7, which are derived from KTC1 and BRAF-inhibitor resistant (Danysh BP et al, 2016). Unlike the other cells evaluated these cells did not have spare respiratory capacity. Additionally, dabrafenib treatment did not alter basal OCR except at the highest doses. Although, we did observe a reduction in glycolysis in the parental KTC1 upon dabrafenib treatment, which was not observed in the KTC1-VA7 cells. Sensitive CUTC5 cells also exhibited a greater decrease in glycolysis than resistant CUTC60 cells. From this, we conclude that glycolysis may contribute to dabrafenib resistance and merits further investigation. With regards to oxidative metabolism, we only observed a reduction in OCR in a dabrafenib sensitive cell line and there was synergistic inhibition in the resistant CUTC60 cells treated with both dabrafenib and rotenone, suggesting that oxidative metabolism aids the cells in tolerating BRAF inhibition. Further screening of dabrafenib sensitive and resistant cells is necessary to determine if this is a function of dabrafenib sensitivity. Citation Format: Eric Bolf, Rebecca Schweppe. BRAF inhibitor resistant thyroid cancer cells exhibit altered cellular energetics [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 2344.