1. BRF0000320900 Begin with BRAF Searching for a target in metastatic melanoma?

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.

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

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

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

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

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

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

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

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

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

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.

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

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