Abstract 5181: Targeted knockdown of MYC in AML cells using G-quadruplex interacting small molecules

Abstract

Abstract Acute Myeloid Leukemia (AML) is a disease that occurs when genomic changes alter expression of key genes, causing cells to resume an undifferentiated state, proliferate, and maintain tumor growth throughout the body. Recently, there has been an increase in efforts toward developing therapies that specifically target the protein products of these aberrantly expressed genes. However, many of the proteins are difficult to target because of structural challenges, protein overexpression that requires high drug doses, or mutations that confer resistance to therapy. One potential type of targeted therapy that circumvents these issues is the use of small molecules that stabilize DNA secondary structures called G-quadruplexes. G-quadruplexes are present in the promoters of many potential oncogenes, and have regulatory roles in their transcription. This study analyzes the therapeutic potential of compounds that target the regulatory G-quadruplex in the MYC oncogene, which is commonly misregulated in AML. Treatment of the MYC expressing AML cell lines KG-1 and UT-7epo with the compound GQC-05 resulted in decreased expression of MYC mRNA, as determined by qPCR. Moreover, GQC-05 treatment induced a more significant decrease in c-Myc protein expression than similar treatment with JQ-1(+), as shown by western blot analysis. Treatment of AML cells with GQC-05 also decreased cell viability and increased apoptosis. Concurrent treatment of AML cells with GQC-05 and JQ-1(+) showed an antagonistic effect, indicating potential competition in the silencing of MYC. These results demonstrate that targeting the MYC promoter G-quadruplex in AML cells leads to knockdown of MYC expression and induces apoptosis. These results further support the development of a novel mechanism for targeting key genetic drivers in AML, and lay the groundwork for advances in treatment of other cancers driven by G-quadruplex regulated oncogenes. Citation Format: Megan A. Turnidge, Apurvi Patel, Justin J. Montoya, David W. Lee, Daniel H. Wai, Vijay Gokhale, Laurence Hurley, Robert J. Arceci, David O. Azorsa. Targeted knockdown of MYC in AML cells using G-quadruplex interacting small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5181. doi:10.1158/1538-7445.AM2017-5181