 2013 Genentech USA, Inc. All rights reserved. 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. BIO

 2013 Genentech USA, Inc. All rights reserved. 2 Apoptosis How do oncogenes and tumor-suppressor genes drive tumorigenesis? Oncogenes and tumor-suppressor genes Dysregulated cell signaling Angiogenesis Proliferation through growth signaling Cell cycle control mechanisms DNA RNA Aberrant or absent protein function Cooper GM. The Cell—A Molecular Approach. 2nd ed. Sunderland, MA: Sinauer Associates, Inc; Vogelstein B, Kinzler KW. Nat Med. 2004;10: Hanahan D, Weinberg RA. Cell. 2011;144: 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: Notes

 2013 Genentech USA, Inc. All rights reserved. 3 Tumors as an organ system Complex physiologic interactions Immune system involvement Vasculature Stromal cell and basement membrane involvement T and B lymphocytes Fibroblast Blood vessel Hanahan D, Weinberg RA. Cell. 2011;144: Natural killer cell Macrophage 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: Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9: Notes

 2013 Genentech USA, Inc. MBoC Program 4 Mechanisms of targeted therapy ADC=antibody-drug conjugate. Ingle GS, et al. Br J Haematol. 2008;140: Antibody-drug conjugates Receptor-ADC complex is internalized into cell ADC binds to the cell-surface receptor Potent cytotoxic agent is released once inside the cell 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: Notes

 2013 Genentech USA, Inc. All rights reserved. 5 Aberrant signaling in cancer can be turned off by targeted therapy AKT PDK1 Cell cycle control Proliferation ↓ Apoptosis ↑ Survival Angiogenesis Cyclin D1 p27 BAD GSK3  NFκB mTOR 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: Rowinsky EK. Oncologist. 2003;8(3):5-17. Trusolino L, et al. Nat Rev Mol Cell Biol. 2010;11: PTEN Sos Grb2ShcRAS RAF MEK MAPK GAB1 PI3K Grb2 STAT3 NFκB MAPK HER3 HER2 MET PI3K 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: 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: Notes