The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy

Abstract

Melanoma is the most serious type of skin cancer and one of the most common cancers in the world. Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival rates. Vemurafenib is a small molecule inhibitor of the BRAF serine-threonine kinase recently approved by the United States Food and Drug Administration to treat patients with metastatic and unresectable melanomas that carry an activating BRAF (V600E) mutation. Many clinical trials evaluating other therapeutic uses of vemurafenib are still ongoing. The ATP-binding cassette (ABC) transporters are membrane proteins with important physiological and pharmacological roles. Collectively, they transport and regulate levels of physiological substrates such as lipids, porphyrins and sterols. Some of them also remove xenobiotics and limit the oral bioavailability and distribution of many chemotherapeutics. The overexpression of three major ABC drug transporters is the most common mechanism for acquired resistance to anticancer drugs. In this review, we highlight some of the recent findings related to the effect of ABC drug transporters such as ABCB1 and ABCG2 on the oral bioavailability of vemurafenib, problems associated with treating melanoma brain metastases and the development of acquired resistance to vemurafenib in cancers harboring the BRAF (V600E) mutation.

Insights into the Phosphoryl Transfer Mechanism of Human Ubiquitous Mitochondrial Creatine Kinase

“…Through the reversible conversion between creatine and phosphocreatine, which is coupled to the equilibrium between ATP and ADP, CK helps maintain energy homeostasis in tissues, which is in need of fluctuating high energy supply12. Because of its essential role in cell cycle regulation, CK is considered to be a potential clinical biomarker and therapeutic target of various illnesses345.…”

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

“…ABCB1, coded by ABCB1 gene, is composed of two homologous halves, each containing six transmembrane domains and an ATP binding/utilization domain, separated by a flexible polypeptide linker (10). ABCB1 renders MDR in cancer cells by transporting a wide spectrum of compounds including the vinca alkaloids [vinblastine and vincristine (VCR)], the anthracyclines [doxorubicin (DOX) and daunorubicin], epipodophyllotoxins, taxanes, and some tyrosine kinase inhibitors (TKI) out of the cells (11,12). The overexpression of ABCB1 could predict poor prognosis of cancer patients (13)(14)(15).…”

Resistance of melanoma cells to anticancer treatment: a role of vascular endothelial growth factor

“…Basic structural elements of the ABC protein are as follows: nucleotide binding domains (NBDs) and transmembrane domains (TMDs). TMDs are responsible for specificity of transported substrates and NBDs for ATP binding and hydrolysis [57]. A phenomenon of resistance to anticancer agents is considered to be the main function of ABC transporters in progression of oncological diseases.…”