Lansoprazole and its Metabolites in the Treatment of TNBC and the Contribution of ABCG2 to CC-115 Resistance

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with a dismal prognosis. Targeted therapies for breast cancer with expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are currently available; however, due to the lack of ER, PR, and HER2 in TNBC, targeted therapies are limited. While surgery and traditional chemotherapy remain the standard of care, development of a new treatment strategy for TNBC is needed to improve clinical outcomes. Fatty acid synthase (FASN) has been implicated as a metabolic oncogene and has given cancer cells a survival advantage by increasing NHEJ repair. Recently, it has been shown that FDA-approved proton pump inhibitors, used for the treatment of acid related digestive diseases, have antitumor effects. Here, I show that a metabolite of lansoprazole, 5-hydroxy lansoprazole sulfide, has increased potency over parent compound lansoprazole. 5-hydroxy lansoprazole sulfide inhibits FASN, leading to a decrease in PARP and NHEJ DNA repair activity in TNBC. Ultimately, this leads to an increase in DNA damage and cell death via apoptosis. These findings suggest that 5-hydroxy lansoprazole sulfide, as a metabolite of lansoprazole, may have better activity in suppressing TNBC cells and that 5-hydroxy lansoprazole sulfide may be developed as a therapeutic for TNBC treatment. Furthermore, due to the role of FASN in increasing NHEJ repair, we hypothesized that FASN played a role in resistance to CC-115, a dual mTOR/DNA-PK inhibitor currently in clinical trials, by increasing DNA-PK activity. However, it was found that ABCG2, an ATP-binding cassette transporter, and not FASN, has a role in CC-115 resistance. ABCG2 effluxes CC-115 from cancer cells, increasing resistance to treatment. Inhibition of ABCG2 by FTC or PZ39C8 led to accumulation of CC-115 within cells and sensitization to treatment. Therefore, ABCG2 status should be assessed to stratify patients into treatment groups, increasing the efficacy of CC-115 treatment.