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Disclosure/Disclaimer. The Molecular Basis of Cancer (MBoC ): Fundamental and Evolving Concepts slide presentation is not an independent educational program, and no CME credits will be provided.

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  1. Disclosure/Disclaimer • The Molecular Basis of Cancer (MBoC): Fundamental and Evolving Concepts slide presentation is not an independent educational program, and no CME credits will be provided. This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development. • The contents of this slide presentation are owned solely by Genentech; any unauthorized uses are prohibited. • This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. • The following slides are selected samples from a complete presentation. They are for educational purposes only. BIO0002078200 1

  2. How do oncogenes and tumor-suppressor genes drive tumorigenesis? Notes The path toward tumorigenesis begins with genes and ends with proteins. Dysregulated cellular signaling is an integral step toward cancer development and a primary mechanism leading to it. Reference: Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. DNA Oncogenes and tumor-suppressor genes RNA Aberrant or absent protein function Apoptosis Angiogenesis Proliferation through growth signaling Cell cycle control mechanisms Dysregulated cell signaling Cooper GM. The Cell—A Molecular Approach. 2nd ed. Sunderland, MA: Sinauer Associates, Inc; 2000. Vogelstein B, Kinzler KW. Nat Med. 2004;10:789-799. Hanahan D, Weinberg RA. Cell. 2011;144:646-674. 2

  3. Tumors as an organ system Notes Complex physiologic interactions • Immune system involvement • Vasculature • Stromal cell and basement membrane involvement The view of tumor growth has broadened to include how tumor cells interact with the surrounding environment to promote tumorigenesis. Depending upon the biological context, the tumor microenvironment may offer a positive or a negative influence on tumor growth.1,2 References: 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. 2. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239-252. Fibroblast Natural killer cell Macrophage T and B lymphocytes Blood vessel 3 Hanahan D, Weinberg RA. Cell. 2011;144:646-674.

  4. Mechanisms of targeted therapy Notes Antibody-drug conjugates ADC binds to the cell-surface receptor Antibody-drug conjugates (ADCs) comprise tumor-specific antibodies linked to anticancer agents.ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure. References: Ingle GS, Chan P, Elliott JM, et al. High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. Br J Haematol. 2008;140:46-58. Receptor-ADC complex is internalized into cell Potent cytotoxic agent is released once inside the cell ADC=antibody-drug conjugate. Ingle GS, et al. Br J Haematol. 2008;140:46-58. 4

  5. AKT RAS Sos Grb2 Grb2 GAB1 Shc STAT3 PI3K PI3K PDK1 RAF PTEN GSK3b NFκB mTOR MEK MAPK MAPK BAD Cyclin D1 p27 Aberrant signaling in cancer can be turned off by targeted therapy Notes HER2 HER3 MET Tryosine kinase (TK) receptor activation drives many pathways leading to activation of targeted genes within the nucleus that can result in cell proliferation.1,2 References: 1. Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159-3167. 2. Rowinsky EK. The ErbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:433-457. NFκB ↓Apoptosis ↑Survival Cell cyclecontrol Angiogenesis Proliferation HER2=human epidermal growth factor receptor-2; HER3=human epidermal growth factor receptor-3; PI3K=phosphatidylinositol 3-kinase; GAB1=Grb2-associated binding protein 1; Grb2=growth factor receptor-bound protein 2; STAT3=signal transducer and activator of transcription 3; RAS=rat sarcoma; Sos=son of sevenless; PDK1=phosphoinositide-dependent kinase-1; PTEN=phosphatase and tensin homolog; RAF=rapidly accelerating fibrosarcoma; MEK=mitogen-activated protein kinase kinase; MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; BAD=-2–associated death promoter; NFκB=nuclear factor kappa–light-chain enhancer of activated B cells; GSK3β=glycogen synthase kinase 3 beta.Olayioye MA, et al. EMBO J. 2000;19:3159-3167.Rowinsky EK. Oncologist. 2003;8(3):5-17. Trusolino L, et al. Nat Rev Mol Cell Biol. 2010;11:834-848. 5

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