2013 Genentech USA, Inc. All rights reserved.

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The Molecular Basis of Lung Cancer 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.

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information presented is consistent with FDA guidelines.

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They are for educational purposes only.

BIO00020782001

2013 Genentech USA, Inc. MBoC Program 2

Angiogenesis is a function of multiple signals from multiple cell types

PericytePDGF, TGFβ

Paracrinefactors

VEGF, Ang-2, bFGF

Endothelial cell

Tumor cell

O2

Nutrients

PDGF=platelet-derived growth factor; TGFβ=transforming growth factor beta; VEGF=vascular endothelial growth factor; Ang-2=angiopoietin; bFGF=basic fibroblast growth factor.

Angiogenesis is a vital process in the progression of cancer from small, localized neoplasms to larger and potentially metastatic tumors. Angiogenic vessels deliver oxygen, nutrients, and survival factors to cancer cells.1,2

References:1. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor

pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027.

2. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-410.

Notes

2013 Genentech USA, Inc. MBoC Program

Types of ALK resistance in ALK+ NSCLC

ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer.Camidge DR, Doebele RC. Nat Rev Clin Oncol. 2012;9:268-277.

Separate oncogene driveras a new tumor clone

Second oncogene driverin the same tumor cell

Primary mutation

Second oncogene (partially ALK dependent)

Separate oncogene (ALK independent)

Primary mutation

3

2013 Genentech USA, Inc. MBoC Program

• Exon 19-21 mutations account for 90% of EGFR mutations

• These mutations increase survival signaling through AKT and STAT but not MAPK proliferation signaling– As a result, the tumor cell

is dependent on survival signaling

• T790M is associated with resistance

Secondary mutation:T790M, ATP-binding pocket• Occurs only after primary activating mutation

L858RNSCLC (45%)

DeletionsNSCLC (45%)

Catalytic domain

EGFR variant III deletionsSCC (5%)

SubstitutionsNSCLC (5%)

Constitutive EGFR-mediated signaling is a major pathogenic mechanism of NSCLC

EGFR=epidermal growth factor receptor; NSCLC=non-small cell lung cancer; MAPK=mitogen activated protein kinase; ATP=adenosine triphosphate.Gazdar AF, et al. Trends Mol Med. 2004;10:481-486. 4