Indiana University-Purdue University Indianapolis (IUPUI) / 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. / 2020-02-21
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/20541 |
| Date | 08 1900 |
| Creators | Beebe, Jennifer Diane |
| Contributors | Zhang, Jian-Ting, Jerde, Travis, Safa, Ahmad, Xie, Jingwu, Fishel, Melissa |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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