BRF0000320900 Begin with BRAF Searching for a target in
metastatic melanoma?
Slide 2
BRF0000320900 Overview Oncogenic BRAF can result from mutations
in the BRAF gene, which may cause the protein to become overactive
1 One common BRAF mutation (BRAF V600 ) is implicated in diverse
malignancies 2,3 Genentech is currently researching oncogenic BRAF
as a novel therapeutic target 2 1. Sharma et al. Cancer Res.
2005;65:2412-2421. 2. Wong. Recent Pat Anticancer Drug Discov.
2009;4:28-35. 3. Wellbrock et al. Biochem Pharmacol.
2010;80:561-567.
Slide 3
BRF0000320900 Table of contents The role of RAS-RAF proteins in
the RAS-RAF pathway The BRAF protein kinase Oncogenic BRAF
Targeting oncogenic BRAF 3
Slide 4
BRF0000320900 The role of RAS-RAF proteins in the RAS-RAF
pathway 4 1. Wong. Recent Pat Anticancer Drug Discov. 2009;4:28-35.
2. Wan et al. Cell. 2004;116:855-867. 3. McCubrey et al. Adv Enzyme
Regul. 2006;46:249-279. RAS BRAF ERK MEK RAF proteins play a role
in the regulation of essential biologic functions 1-3 Cell growth
Cell proliferation Cell differentiation
Slide 5
BRF0000320900 RAS-RAF signaling in normal cells 5 1. McCubrey
et al. Adv Enzyme Regul. 2006;46:249-279. Activation of the RAS-RAF
signaling cascade occurs via the following sequential steps 1 :
Activation by growth factors Activation of RAS Activation of RAF
Phosphorylation of MEK Phosphorylation of ERK Activation of
transcription factors Result 1 Cell proliferation Cell
survival
Slide 6
BRF0000320900 Table of contents The role of RAS-RAF proteins in
the RAS-RAF pathway The BRAF protein kinase Oncogenic BRAF
Targeting oncogenic BRAF 6
Slide 7
BRF0000320900 The BRAF protein kinase 7 1. Wan et al. Cell.
2004;116:855-867. BRAF is a protein kinase encoded by the BRAF gene
and plays an important role as an intermediary in the RAS-RAF
signaling cascade 1
Slide 8
BRF0000320900 Table of contents The role of RAS-RAF proteins in
the RAS-RAF pathway The BRAF protein kinase Oncogenic BRAF
Targeting oncogenic BRAF 8
Slide 9
BRF0000320900 Oncogenic BRAF 1. McCubrey et al. Adv Enzyme
Regul. 2006;46:249-279. 2. Pritchard et al. Biochem Soc Trans.
2007;35:1329-1333. 3. Cho et al. Int J Cancer. 2006;119:1858-1862.
V600E mutation BRAF mutations at position 600 (BRAF V600 ) can lead
to overactive BRAF signaling 1 The most common BRAF mutation, BRAF
V600E, is implicated in: ~50% of melanoma tumors 1 ~40% of
papillary thyroid tumors 1,2 ~30% of serous ovarian tumors 2 ~10%
of colorectal tumors 3 ~10% of prostate tumors 3 9
Slide 10
BRF0000320900 Oncogenic BRAF signaling 10 1. Wong. Recent Pat
Anticancer Drug Discov. 2009;4:28-35. 2. McCubrey et al. Adv Enzyme
Regul. 2006;46:249-279. Excessive cell proliferation Resistance to
apoptosis An overactive signaling cascade 1 Independent of growth
factors Uncontrolled signaling Result 1,2
Slide 11
BRF0000320900 Table of contents The role of RAS-RAF proteins in
the RAS-RAF pathway The BRAF protein kinase Oncogenic BRAF
Targeting oncogenic BRAF 11
Slide 12
BRF0000320900 Research into oncogenic BRAF Research is
currently ongoing to detect and target oncogenic BRAF Inhibition of
oncogenic BRAF is an opportunity for precise molecular targeting 1
Research efforts are also underway to use molecular biology
techniques to detect the BRAF V600 mutation 2 12 1. Wellbrock et
al. Biochem Pharmacol. 2010;80:561-567. 2. Lin et al. Br J Cancer.
2011;104:464-468.
Slide 13
BRF0000320900 Overview of metastatic melanoma disease state 13
1. Bhatia et al. Oncology. 2009;23:488-496. 2. Korn et al. J Clin
Oncol. 2008;26:527-534. 3. McCubrey et al. Adv Enzyme Regul.
2006;46:249-279. 4. Skarin, ed. Atlas of Diagnostic Oncology. 4th
ed. Philadelphia, PA: Mosby, Inc; 2010:467. Metastatic melanoma is
an important area for continued research and development of
strategies for patient management Median overall survival of ~8
months 1 1-year survival rate of ~25% 2 ~50% of metastatic melanoma
tumors have the BRAF V600 mutation 3 Reprinted with permission from
Elsevier. 4
Slide 14
BRF0000320900 References Bhatia S, Tykodi SS, Thompson JA.
Treatment of metastatic melanoma: an overview. Oncology.
2009;23:488-496. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH.
BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer.
2006;119:1858-1862. Korn EL, Liu PY, Lee SJ, et al. Meta-analysis
of Phase II cooperative group trials in metastatic stage IV
melanoma to determine progression-free and overall survival
benchmarks for future Phase II trials. J Clin Oncol.
2008;26:527-534. Lin J, Goto Y, Murata H, et al. Polyclonality of
BRAF mutations in primary melanoma and the selection of mutant
alleles during progression. Br J Cancer. 2011;104:464-468. McCubrey
JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and
PI3K/PTEN/AKT pathways in malignant transformation and drug
resistance. Adv Enzyme Regul. 2006;46:249-279. Pritchard C,
Carragher L, Aldridge V, et al. Mouse models for BRAF-induced
cancers. Biochem Soc Trans. 2007;35:1329-1333. Sharma A, Trivedi
NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP. Mutant V599E
B-raf regulates growth and vascular development of malignant
melanoma tumors. Cancer Res. 2005;65:2412-2421. Skarin AT, ed.
Atlas of Diagnostic Oncology. 4th ed. Philadelphia, PA: Mosby, Inc;
2010:467. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of
activation of the RAF-ERK signaling pathway by oncogenic mutations
of B-RAF. Cell. 2004;116:855-867. Wellbrock C, Hurlstone A. BRAF as
therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567.
Wong KK. Recent developments in anti-cancer agents targeting the
Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov.
2009;4:28-35. 14