Therapeutic targeting of the ATP7A copper transporter in cancer
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[EMBARGOED UNTIL 12/01/2026] Copper (Cu) is an essential micronutrient involved in numerous biochemical processes, including energy production, iron metabolism, cell proliferation, cuproenzyme activity, and collagen crosslinking. Because Cu cannot be synthesized or metabolized by the body, it must be obtained through diet or supplementation. As a redox-active metal, Cu cycles between cuprous (Cu⁺) and cupric (Cu²⁺) states, making it a critical cofactor for various cuproenzymes. However, this same redox activity renders free Cu ions highly cytotoxic within the cytosol. To mitigate this, cells have evolved to control Cu uptake, intracellular distribution, and export. The high-affinity Cu transporter 1 (CTR1) mediates cellular Cu uptake, while the P1B-type ATPase ATP7A facilitates Cu transport from the cytosol into the lumen of vesicles or the trans-Golgi network (TGN), where it metalates cuproenzymes such as the lysyl oxidase (LOX) family and tyrosinase. Under elevated Cu conditions, ATP7A undergoes Cu-stimulated trafficking to the plasma membrane to export excess Cu into the extracellular space. Studies have shown that many cancer cells exhibit increased Cu demand. Elevated Cu levels have been linked to enhanced kinase activity of MEK1/2 and ULK1/2, promoting tumor growth in BRAF- and KRAS-driven cancers. Cu has also been reported to induce unfolding of the tumor suppressor protein p53 and to drive invasion and chemoresistance in various cancer types. The heightened metabolic demand for Cu in cancer cells is a vulnerability that can be explored in cancer-targeted therapeutic solutions. Several studies have demonstrated that Cu chelation using agents such as penicillamine, trientine, tetrathiomolybdate, and tetraethylenepentamine, significantly reduces primary tumor growth, metastasis, and angiogenesis in preclinical cancer models. However, clinical trials using these chelators have yet to yield viable cancer therapies. The first part of this dissertation explores an alternative systemic Cu depletion strategy by targeting intestinal Cu absorption through deletion of the Atp7a gene. We demonstrate that intestinal Atp7a deletion in C57BL/6 mice, eliminates ATP7A protein expression in the small intestine, induces systemic Cu deficiency, and reduces Cu levels in both LLC and B16 primary tumors. Furthermore, we show that this targeted Atp7a deletion enhances the therapeutic efficacy of the Cu chelator tetrathiomolybdate in suppressing tumor growth in both B16 and LLC tumor models, and spontaneous metastasis in the LLC tumor model. In addition to its role in Cu homeostasis, ATP7A is implicated in the development of chemoresistance in various cancers. Deletion of Atp7a in RAS-transformed mouse embryonic fibroblasts (MEFs) increases sensitivity to cisplatin in vivo. ATP7A and its homolog ATP7B are thought to confer chemoresistance by sequestering drugs in vesicles or the TGN, although the precise mechanisms remain under debate. The second part of this dissertation investigates the roles of ATP7A functions in the development of chemoresistance in 4T1 TNBC cells and the underlying mechanisms. Using a novel small-molecule ATP7A inhibitor, MKV3, we show that ATP7A inhibition significantly reduces cellular GSH levels, enhances doxorubicin (DOX) sensitivity, and reverses DOX resistance. Additionally, ATP7A inhibition increases nuclear DOX accumulation, reduces DOX efflux, and promotes DOX-induced aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) proteins in 4T1 TNBC cells. Altogether, these studies support ATP7A as a promising therapeutic target for both cancer treatment and the reversal of acquired chemoresistance.
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Ph. D.