A Pharmacological Investigation of the Interaction of Major Drug Resistance-Associated ATP-Binding Cassette Proteins with Vemurafenib and Braf Inhibitors in Wild-Type and BRAF(V600E) Mutant Cancers

A major cause of death in cancer is due to metastasis that are resistant to conventional therapy. Multidrug resistance (MDR) caused by the overexpression of ATP-Binding Cassette (ABC) drug transporters is a major obstacle in clinical cancer chemotherapy. Of all types of skin cancer, malignant melanoma has the highest potential for metastasis and very low survival rates. Vemurafenib (Zelboraf) was the first potent BRAF(V600E) signaling inhibitor approved by the US Food and Drug Administration in 2011 for the treatment of metastatic and unresectable melanomas that carry an activating BRAF(V600E) mutation. Vemurafenib inhibits the constitutively activated BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients. Vemurafenib was extremely effective in treating advanced melanoma patients and was thus sought to be used on BRAF(V600E) mutant colorectal and thyroid cancers. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. Therefore, like in most cancer chemotherapies, identification of potential mechanisms of cellular resistance and overcoming acquired resistance to vemurafenib presents a significant therapeutic challenge. The most common mechanism for acquired resistance in cancer chemotherapy is associated with the overexpression of three members of the ABC transporter family: ABCB1, ABCC1 and ABCG2. Therefore, we have fully characterized the interactions of vemurafenib with major ABC transporters in our most recent study. We were the first to revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is significantly reduced in BRAF(V600E) mutant A375 melanoma cells. Moreover, we discovered that vemurafenib is capable of directly inhibiting the function of and restores drug sensitivity in ABCG2-overexpressing MDR cancer cells. The objective of this proposal is to investigate the overall impact of major ABC drug transporters on the therapeutic effectiveness of vemurafenib and new BRAF inhibitors in both wild-type BRAF and BRAF(V600E) mutant cancers. To start with, we will determine whether (1) the overexpression of ABCG2 also confers resistance to vemurafenib in BRAF(V600E) mutant colorectal and thyroid cancers. To enable us to reveal the true relevance of ABC drug transporter on the development of acquired resistance to vemurafenib in BRAF(V600E) mutant cancers, we will (2) generate vemurafenib resistant BRAF(V600E) mutant cancer cell lines and ABC transporter-positive BRAF(V600E) mutant cancer cell lines via various drug selection regiments. Moreover, we will also (3) evaluate various combination chemotherapies targeting multiple pathways in order to overcome acquired vemurafenib resistance in cancers harboring the BRAF(V600E) mutation. Lastly, we will examine (4) the interactions between drug resistant-associated ABC proteins and new BRAF inhibitors or inhibitors that are still in clinical trials. We will also (5) evaluate the use of vemurafenib and new BRAF inhibitors as high-affinity modulators to restore drug sensitivity in ABC transporter-positive MDR cancers.

Project ID:PC10207-0435
External Project ID:NSC102-2320-B182-036