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Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells.
Biochem Pharmacol. 2013 Feb 01; 85(3):325-34.BP

Abstract

Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan 333, Taiwan. wuchung@mail.cgu.edu.twNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23153455

Citation

Wu, Chung-Pu, et al. "Overexpression of ATP-binding Cassette Transporter ABCG2 as a Potential Mechanism of Acquired Resistance to Vemurafenib in BRAF(V600E) Mutant Cancer Cells." Biochemical Pharmacology, vol. 85, no. 3, 2013, pp. 325-34.
Wu CP, Sim HM, Huang YH, et al. Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Biochem Pharmacol. 2013;85(3):325-34.
Wu, C. P., Sim, H. M., Huang, Y. H., Liu, Y. C., Hsiao, S. H., Cheng, H. W., Li, Y. Q., Ambudkar, S. V., & Hsu, S. C. (2013). Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Biochemical Pharmacology, 85(3), 325-34. https://doi.org/10.1016/j.bcp.2012.11.003
Wu CP, et al. Overexpression of ATP-binding Cassette Transporter ABCG2 as a Potential Mechanism of Acquired Resistance to Vemurafenib in BRAF(V600E) Mutant Cancer Cells. Biochem Pharmacol. 2013 Feb 1;85(3):325-34. PubMed PMID: 23153455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. AU - Wu,Chung-Pu, AU - Sim,Hong-May, AU - Huang,Yang-Hui, AU - Liu,Yen-Chen, AU - Hsiao,Sung-Han, AU - Cheng,Hsing-Wen, AU - Li,Yan-Qing, AU - Ambudkar,Suresh V, AU - Hsu,Sheng-Chieh, Y1 - 2012/11/12/ PY - 2012/10/04/received PY - 2012/11/05/revised PY - 2012/11/06/accepted PY - 2012/11/17/entrez PY - 2012/11/17/pubmed PY - 2013/3/21/medline SP - 325 EP - 34 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 85 IS - 3 N2 - Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/23153455/Overexpression_of_ATP_binding_cassette_transporter_ABCG2_as_a_potential_mechanism_of_acquired_resistance_to_vemurafenib_in_BRAF_V600E__mutant_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(12)00728-9 DB - PRIME DP - Unbound Medicine ER -