Introduction: A major obstacle in the treatment of cancers is innate or acquired resistance. Multi-drug resistance proteins such as MDR1, ABCG2, MRP1, and LRP have been shown to be involved in resistance and are predictors of clinical outcomes. Expression of ABCG2, an ATP-binding cassette efflux transporter, may be responsible for observed variability of the efficacy of CC-115, a dual mTOR/DNA-PK inhibitor, currently in clinical trials. Here we evaluate the role of ABCG2 in CC-115 resistance.
Methods: Western blots, methylene blue and MTT assays, and FACS were used to determine ABCG2 expression, cell survival/viability with and without inhibitors, and accumulation of CC-115 respectively.
Results: MCF7/AdVp3000 (M3K) cells have been shown to have a significant increase in ABCG2 as compared to parental MCF7 cells. M3K cells had a 50-fold increase in IC50 to CC-115 compared to MCF7. Use of ABCG2 inhibitors FTC and C8 (1uM), decreased the IC50 of CC-115 in M3K cells by 10-fold. Accumulation studies using FACS showed that M3K cells had significantly lower accumulation of CC-115 as compared to MCF7 and addition of FTC and C8 (1uM) significantly enhanced accumulation of CC-115 to the same extent as seen in MCF7 cells. Next, HEK293/ABCG2 stable clone with overexpression of ectopic ABCG2 and its control HEK293/vec cells were used to determine ABCG2's direct impact on CC-115 resistance. HEK293/ABCG2 cells had a 10-fold increase in resistance to CC-115 with an IC50 of 2.05 uM as compared to 0.23 uM in HEK293/vec cells. Addition of FTC and C8 (1uM) decreased the IC50 by 10-fold in HEK293/ABCG2 cells. Accumulation of CC-115 in HEK293/ABCG2 cells was also significantly lower than that in HEK293/vec cells and addition of FTC and C8 (1uM) significantly increased its accumulation only in HEK293/ABCG2 cells.
Discussion: The results from this study suggest that ABCG2 contributes to and possibly is responsible for CC-115 resistance and that inhibiting ABCG2 could lead to reversal of CC-115 resistance, increased response rate, highlights the importance of personalized therapies, and has the potential to increase patient survival.
Citation Format: Jenny Beebe. ABCG2 expression contributes to CC-115 resistance [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 5891.