Targeting ATP-citrate lyase (ACLY) to overcome therapy resistance in breast cancer and melanoma

Pace University New York, New York NY

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Abstract

SUMMARY The use of small molecule kinase inhibitors that target specific enzymes overactive in cancer cells has revolutionized cancer patient treatment. To treat some types of breast cancer, CDK4/6 inhibitors have been developed that target the phosphorylation of the Rb tumor suppressor gene. These inhibitors have been approved by the FDA and are used in combination with hormonal therapies. Similarly, in melanoma, the recently approved BRAF and MEK inhibitors target the MAPK growth stimulatory pathway to impair cancer progression. While these therapies exhibit clear patient responses initially, the development of acquired resistance occurs when the cancer cells subvert the action of the kinase inhibitor by activating alternate pathways that stimulate tumorigenesis. For example, the AKT pro- survival signaling pathway is often activated in response to targeted therapy, and stimulates resistance to the initial treatment. AKT plays various roles in promoting cancer by stimulating growth, metastasis, and changes in metabolism that support rapid cell proliferation. In this project we will focus on AKT- mediated stimulation of ATP-citrate lyase (ACLY), an enzyme that links high glycolytic activity in cancer cells with increased lipid synthesis required for the production of cell membranes. ACLY expression and activity is abnormal in several types of tumors, and is a newly identified target in drug development. These studies will determine the efficacy of combining ACLY inhibition with CDK4/6 inhibition in breast cancer or BRAF/MEK inhibition in melanoma on tumorigenesis; namely with respect to cell proliferation, apoptosis and invasiveness. The project will be carried out by undergraduate researchers at Pace University and may yield useful information that could inform the development of future therapies aimed at the reduction of acquired resistance and improve patient care.