Targeted Drug Therapies for BRAF Mutated Tumors
Keywords:
MedicineAbstract
Mutations in the Ras/Raf/MEK/ERK pathway are frequently present in human cancer. Following extracellular signaling, the G protein Ras becomes activated which further leads to activation of a member of the Raf kinase family. Subsequent activation of other cascade members, such as MEK (MAP/ERK kinase) and ERK (extracellular signal-regulated kinase) eventually results in the activation of transcription factors, which regulate key cellular processes such as growth, differentiation, and apoptosis. The v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) is frequently mutated in a range of human cancers including melanoma, papillary thyroid carcinoma, and colorectal carcinoma. Consequently, BRAF has been identified as a therapeutic drug target with the development of BRAF inhibitors in recent years. Researchers are focusing on understanding the resistance mechanisms present in BRAF-mutated cancers and have identified combination therapy as a potential treatment option that may overcome resistance to BRAF inhibitors. In this review of the literature, the development of BRAF inhibitors and their clinical use is investigated. In addition, resistance to BRAF inhibitors and combination therapy are discussed.
References
2 Robinson, M.J. and M.H. Cobb, Mitogen-activated pro- tein kinase pathways. Curr Opin Cell Biol. 9(2): p. 180-6 (1997).
3 Improta, G., et al., Biological insights into BRAF muta- tions in melanoma patient: Not mere therapeutic targets. Onco- immunology 2(8): p. e25594 (2013).
4 Pratilas, C.A. and D.B. Solit, Targeting the mitogen-acti- vated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res 16(13): p. 3329-34 (2010).
5 Zambon, A., et al., Small molecule inhibitors of BRAF in clinical trials. Bioorg Med Chem Lett 22(2): p. 789-92 (2012).
6 Trunzer, K., et al., Pharmacodynamic effects and mech- anisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 31(14): p. 1767-74 (2013).
7 Yang, H., et al., RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in pre- clinical melanoma models. Cancer Res 70(13): p. 5518-27 (2010).
8 Chapman, P.B., et al., Improved survival with vemu- rafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26): p. 2507-16 (2011).
9 Hauschild, A., et al., Dabrafenib in BRAF-mutated meta- static melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839): p. 358-65 (2012).
10 Gentilcore, G., et al., Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer 13: p. 17 (2013).
11 Goldenberg, M.M., Pharmaceutical approval update. P T 38(11): p. 705-7 (2013).
12 Stuart DD, L.N., Poon DJ, Aaralen K, Kaufman S, Merritt H et al, Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Cancer Res 72(8 Suppl)(8) (2012).
13 FDA., U.S. Sorafenib (NEXAVAR). (2013); Available at: http://www.fda.gov/drugs/informationondrugs/approved- drugs/ucm376547.htm. (Accessed: 25th January 2014)
14 Wilhelm, S.M., et al., BAY 43-9006 exhibits broad spec- trum oral antitumor activity and targets the RAF/MEK/ERK path- way and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19): p. 7099-109 (2004).
15 Clark, J.W., et al., Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor re- ceptor inhibitor, BAY 43-9006, in patients with advanced, refrac- tory solid tumors. Clin Cancer Res 11(15): p. 5472-80 (2005).
16 Wilhelm, S., et al., Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor ac- tivity. International journal of cancer. Journal international du cancer 129(1): p. 245-255 (2011).
17 Clinicaltrials.gov., Safety and Efficacy Study of BMS- 908662 Alone or in Combination With Cetuximab in Subjects With K-RAS or B-RAF Mutation Positive Advanced or Metastatic Colorectal Cancer. (2011); Available at: http://clinicaltrials.gov/ ct2/show/NCT01086267?term=xl281&rank=2. (Accessed: 28th January 2014).
18 Bucheit, A. and M. Davies, Emerging insights into resist- ance to BRAF inhibitors in melanoma. Biochemical pharmacolo- gy 87(3): p. 381-389 (2014).
19 Villanueva, J., et al., Acquired resistance to BRAF inhib- itors mediated by a RAF kinase switch in melanoma can be over- come by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18(6): p. 683-95 (2010).
20 Montagut, C., et al., Elevated CRAF as a potential mech- anism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 68(12): p. 4853-61 (2008)
21 Acquaviva, J., et al., Overcoming Acquired BRAF Inhib- itor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib. Mol Cancer Ther, (2014).
22 Davies, M.A., The role of the PI3K-AKT pathway in mela- noma. Cancer J 18(2): p. 142-7 (2012)
23 Wu, H., V. Goel, and F.G. Haluska, PTEN signaling path- ways in melanoma. Oncogene 22(20): p. 3113-22 (2003).
24 Deng, W., et al., Role and therapeutic potential of PI3K- mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res 25(2): p. 248-58 (2012)
25 Paraiso, K.H., et al., PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res 71(7): p. 2750-60 (2011)
26 Atefi, M., et al., Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One 6(12): p. e28973 (2011)
27 Neckers, L. and S.P. Ivy, Heat shock protein 90. Curr Opin Oncol 15(6): p. 419-24 (2003).
28 Paraiso, K.H., et al., The HSP90 inhibitor XL888 over- comes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res 18(9): p. 2502-14 (2012)
29 Roskoski, R., Jr., ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66(2): p. 105-43 (2012).
30 Solit, D.B., et al., BRAF mutation predicts sensitivity to MEK inhibition. Nature 439(7074): p. 358-62 (2006).
REVIEWS
31 Adjei, A.A., et al., Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26(13): p. 2139-46 (2008).
32 Patel, S.P., et al., Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Can- cer 119(4): p. 799-805 (2013).
33 Catalanotti, F., et al., Phase II trial of MEK inhibi- tor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res 19(8): p. 2257-64 (2013).
34 FDA., U.S. Trametinib and Dabrafenib. (2014); Available at: http://www.fda.gov/Drugs/InformationOnDrugs/Approved- Drugs/ucm381451.htm (Accessed: 2nd February 2014).
35 GlaxoSmithKline. Study ID 113220 results summary. (2013); Available at: http://www.gsk-clinicalstudyregister.com/ study/113220-rs. (Accessed: 2nd February 2014).
36 Flaherty, K.T., et al., Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18): p. 1694-703 (2012).
37 Davies, H., et al., Mutations of the BRAF gene in human cancer. Nature 417(6892): p. 949-54 (2002).
Downloads
Published
How to Cite
Issue
Section
License
Authors retain copyright and grant the journal the right of first publication with the work simultaneously licensed under a Creative Commons Attribution (CC-BY) 4.0 License that allows others to share the work with an acknowledgement of the work’s authorship and initial publication in this journal.
Provided they are the owners of the copyright to their work, authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository, in a journal or publish it in a book), with an acknowledgement of its initial publication in this journal.
