Abstract
V600BRAF mutation was identified as an ideal target for clinical therapy due to its indispensable roles in supporting melanoma initiation and progression. Despite the fact that BRAF inhibitors (BRAFi) can elicit anti-tumor responses in the majority of treated patients and confer overall survival benefits, acquired drug resistance is a formidable obstacle to long-term management of the disease. Several aberrant events including RTK upregulation, NRAS mutation, mutant BRAF amplification or alternative splicing, and MEK mutation have been reported as acquired BRAFi resistance mechanisms. Clinially, detection of these resistance mechanisms help understand drug response patterns and help guide combinatorial therapeutic strategies. Therefore, quick and accurate diagnosis of the resistant mechanisms in tumor biopsies has become an important starting point for personalized therapy. In this chapter, we review the major acquired BRAFi resistance mechanisms, highlight their therapeutic implications, and provide the diagnostic methods from clinical samples.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Davies H, Bignell GR et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Bollag G, Hirth P et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599
Flaherty KT, Puzanov I et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819
Chapman PB, Hauschild A et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516
Hauschild A, Grob J-J et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365
Falchook GS, Long GV et al (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379:1893–1901
Nazarian R, Shi H et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977
Johannessen CM, Boehm JS et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972
Poulikakos PI, Persaud Y et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390
Shi H, Moriceau G et al (2012) Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724
Wagle N, Emery C et al (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085–3096
Villanueva J, Vultur A et al (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–695
Prahallad A, Sun C et al (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483:100–103
Corcoran RB, Ebi H et al (2012) EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2:227–235
Yadav V, Zhang X et al (2012) Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 287:28087–28098
Duncan JS, Whittle MC et al (2012) Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149:307–321
Shi H, Kong X et al (2011) Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res 71:5067–5074
Vigil D, Cherfils J et al (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857
Fedorenko IV, Gibney GT et al (2013) NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene 32(25):3009–3018
Flaherty KT, Infante JR et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703
Kobayashi S, Boggon TJ et al (2005) EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med 352:786–792
Patel SP, Kim KB (2012) Selumetinib (AZD6244; ARRY-142886) in the treatment of metastatic melanoma. Expert Opin Investig Drugs 21:531–539
Emery CM, Vijayendran KG et al (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci 106:20411–20416
Shi H, Moriceau G et al (2012) Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors. Cancer Discov 2:414–424
Dörrie J, Wellner V et al (2006) An improved method for RNA isolation and removal of melanin contamination from melanoma tissue: implications for tumor antigen detection and amplification. J Immunol Method 313:119–128
Lagonigro MS, De Cecco L et al (2004) CTAB-urea method purifies RNA from melanin for cDNA microarray analysis. Pigment Cell Res 17:312–315
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media, New York
About this protocol
Cite this protocol
Lo, R.S., Shi, H. (2014). Detecting Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma. In: Thurin, M., Marincola, F. (eds) Molecular Diagnostics for Melanoma. Methods in Molecular Biology, vol 1102. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-727-3_10
Download citation
DOI: https://doi.org/10.1007/978-1-62703-727-3_10
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-726-6
Online ISBN: 978-1-62703-727-3
eBook Packages: Springer Protocols