Contents. Preface XV Acknowledgments XXI List of Abbreviations XXIII About the Companion Website XXIX

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1 Contents Preface XV Acknowledgments XXI List of Abbreviations XXIII About the Companion Website XXIX 1 General Aspects of Signal Transduction and Cancer Therapy General Principles of Signal Transduction Biological Signals have to be Processed What is a Signal Transduction Pathway? Mechanisms of Direct Signal Transduction The Interactome Gives Insight into the Signaling Network Protein Domains for Protein-Protein Interaction and Signal Transduction Functions of Mutated Proteins in Tumor Cells Drugs against Cancer Terms and Definitions The Steps from a Normal Cell to a Tumor Interference Levels of Therapeutic Drugs Drugs Attacking the Whole Cell DNA Alkylating Drugs Process-Blocking Drugs Drugs Blocking Synthesis of DNA and RNA Drugs Blocking the Synthesis of DNA and RNA Precursor Molecules Drugs Blocking Dynamics of Microtubules Innovative Molecule-Interfering Drugs Fast-Dividing Normal Cells and Slowly Dividing Tumor Cells: Side Effects and Relapse Drug Resistance Drugs Circumventing Resistance Outlook 20 References 21

2 Tumor Cell Heterogeneity and Resistance to Targeted Therapy 23 The Genetic Basis of Tumorigenesis 24 Clonal Heterogeneity 24 Clonal Origin of Tumors 24 Clonal Evolution 26 The Time Course of Clonal Evolution 30 Clonal Evolution and Resistance to Therapy 32 Targeting Essential Drivers (Driver Addiction) 34 Resistance by Alternative Pathway Activation 36 Overcoming Resistance by Combinatorial Therapies 36 Tumor Stem Cells and Tumor Cell Hierarchies 37 Epigenetics and Phenotypic Plasticity 40 Microenvironment 42 Outlook 43 References 44 Cell Cycle of Tumor Cells 47 Properties of Tumor Cells 48 Differences between Tumor Cells and Normal Cells In vitro 49 Regulation of Cell Number 49 The Cell Cycle 50 Checkpoints 51 Cyclins 52 Cyclin-Dependent Kinases (CDKs) 53 The Retinoblastoma-Associated Protein Rb as Regulator of the Cell Cycle 54 Inhibitors of CDKs 54 Checkpoints and DNA Integrity 55 The Repair Mechanism Depends on the Cell Cycle Phase 57 Tumor-Relevant Proteins in the Cell Cycle 57 The Cell Cycle as Therapeutic Target 58 Small Compounds Inhibiting Cell-Cycle-Dependent Kinases as Anticancer Drugs 59 Outlook 60 References 61 Cell Aging and Cell Death 63 A Cells Journey through Life 64 Cellular Aging and Senescence 64 Replicative Senescence 65 Shortening of Chromosomal Telomeres during Replication 67 Chromosomal Telomeres 67 Telomerase 69 Animal Models 72

3 4.2.6 Overcoming Replicative Senescence in Tumor Cells Nonreplicative Senescence Cell Death Morphologies of Dying Cells Morphology of Necrotic Cells Morphologies of Apoptotic and Necroptotic Cells Morphology of Autophagy Necroptosis Apoptosis in the Healthy Organism The Four Phases of Apoptosis Extrinsic Initiation TNF Pathway TNF Receptor Downstream Signaling Caspases Intrinsic Initiation Execution Phase Phagocytosis and Degradation Apoptosis of Tumor Cells Autophagy Autophagy in Tumor Development Regulation of Autophagy Cell Death and Cell Aging as Therapeutic Targets in Cancer Treatment Induction of Apoptosis by Radiation Induction of Apoptosis by Conventional Anticancer Drugs Innovative Drugs Targeting Aging and Death Pathways Targeting TRAIL (TNF-Related Apoptosis-Inducing Ligand) Targeting Bcl Simulating the Effects of ciap Inhibitors Targeting Autophagy Pathways Senescence in Anticancer Therapy Outlook 94 References 95 5 Growth Factors and Receptor Tyrosine Kinases Growth Factors Protein Kinases Receptor Protein Tyrosine Kinases Receptor Protein Tyrosine Kinase Activation The Family of EGF Receptors The Family of PDGF Receptors The Insulin Receptor Family and its Ligands Prostate-Specific Antigen Signaling from Receptor Protein Tyrosine Kinases 108

4 5.2.7 Association of PDGF and EGF Receptors with Cytoplasmic Proteins Signaling from PDGF and EGF Receptors Constitutive Activation of RTKs in Tumor Cells Therapy of Tumors with Deregulated Growth Factors and their Receptors Targeting Growth Factors Targeting EGF Receptors by Antibodies Targeting EGF Receptors by Kinase Inhibitors Outlook 117 References The Philadelphia Chromosome and BCR-ABL Analysis of Chromosomes Aberrant Chromosomes in Tumor Cells The Philadelphia Chromosome Molecular Diagnosis of the BCR-ABL1 Fusion Gene The BCR-ABL1 Kinase Protein Structural Aspects of BCR-ABL1 Kinase Substrates and Effects of BCR-ABL1 Kinase The BCR-ABL1 Kinase Inhibitor Imatinib Imatinib in Treatment of Tumors Other than CML Mechanism of Imatinib Action Resistance against Imatinib BCR-ABL1 Kinase Inhibitors of the Second and the Third Generation Allosteric Inhibitors of BCR-ABL Outlook 133 References MARK Signaling The RAS Gene The Ras Protein The Ras Protein as a Molecular Switch The GTPase Reaction in Wild-Type and Mutant Ras Proteins Neurofibromin: The Second RasGAP Downstream Signaling of Ras The BRaf Protein The BRAF Gene The MAPK Signaling Pathway Mutations in Genes of the MAPK Pathway Therapy of Tumors with Constitutively Active MAPK Pathway Ras as a Therapeutic Target Inhibiting Posttranslational Modification and Membrane Anchoring of Ras 150

5 Direct Targeting Mutant Ras Preventing Ras/Raf Interaction BRaf Inhibitors Consequences of BRaf Inhibition by Vemurafenib S.2.2 Resistance against BRaf Inhibitors Based on BRaf Dependent Mechanisms Z Resistance against BRaf Inhibitors Based on BRaf Independent Mechanisms Treatment of Vemurafenib-Resistant Tumors Outlook 156 References PI3K-AKT-mTOR Signaling Discovery of the PI3I<-AI<T-mTOR Pathway Phosphatidylinositol-3-Kinase (PI3K) Inositol Trisphosphate, Diacylglycerol, and Protein Kinase C (PKC) Protein Kinase C (PKC) Activation and Functions of PKC AKT (Protein Kinase B) mtor mtorcl: Inputs mtorc2: Inputs mtorcl: Outputs mtorc2: Outputs Feedback Controls PTEN Activation of the PI3K/AI<T/mTOR Pathway in Cancer Sporadic Carcinomas Hamartoma Syndromes PKC in Cancer Therapy Outlook 178 References Hypoxia-Inducible Factor (HIF) Responses of HIF to Hypoxia and Oncogenic Pathways HIF Functional Domains Regulation of HIF Regulation of HIF under Normoxic Conditions Regulation of HIF under Hypoxic Conditions Oxygen-Independent Regulation of HIF Context-Dependence of HIF Regulation Regulation of HIF in Malignant Disease Expression of HIF in Human Tumors 191

6 9.4.2 von Hippel-Lindau Disease HIF Targets in Cancer Target Genes of HIFI«and HIF2ct HIF Target Genes Affecting Tumor Growth HIF Target Genes Affecting Metabolism i Glucose Uptake and Metabolism HIFloc and the Warburg Effect The Warburg Paradox TCA Cycle Intermediates and Tumor Syndromes Drugs Targeting HIFs Outlook 202 References NF-kB Pathways NF-kB Signaling in Inflammation, Growth Control, and Cancer The Core of NF-kB Signaling Family of IkB Proteins Canonical NF-kB Signaling from TNF Receptor B-Cell Receptor Signaling Other Receptors Activating the Canonical Pathway Alternative NF-kB Pathway Terminating the NF-kB Response Ubiquitinylation in NF-kB Signaling Transcriptional Regulation Physiological Role of NF-kB Transcription Factors Mutational Activation of NF-kB Pathways in Malignant Disease B-Cell Lymphomas Multiple Myeloma Activation of NF-kB Pathways by Polycomb-Mediated Loss of microrna-31 in Adult T-Cell Leukemia/Lymphoma Carcinomas Cross Talk between Mutant KRas and NF-kB Inflammation, NF-kB, and Cancer Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases Targeting NF-kB Pathways B-Cell Malignancies Carcinomas Anti-Inflammatory Drugs Outlook 233 References 234

7 11 Wnt Signaling The History of Wnt The Canonical Wnt Pathway The Nonactivated Wnt Pathway The Physiologically Activated Wnt Pathway The Nonphysiologically Activated Wnt Pathway in the Absence of the Wnt Signal The Wnt Network Proteins of the Wnt Pathway with Diverse Functions APC (Adenomatous Polyposis Coli Protein) ß-Catenin Axin The Wnt Targe tome The Three Levels of the Wnt Targetome Biological Effects of Wnt Target Genes The Wnt Pathway as Therapeutic Target Strategies to Identify Anti-Wnt Drugs Molecules Interfering with the Wnt Pathway Outlook 254 References Notch Signaling Introduction Determination of Cell Fate Decisions Notch Proteins and Notch Ligands Notch Signaling The Notch Signaling Pathway Regulation of Notch Signaling by Posttranslational Modification Ubiquitinylation Glycosylation of Notch Notch Signaling in Malignant Disease Acute T-Cell Leukemia (T-ALL) Chronic Lymphocytic Leukemia Chronic Myelomonocytic Leukemia (CMML) Breast Cancer Cholangiocellular Carcinoma (CCC) Squamous Cell Carcinomas (SCCs) Small-Cell Lung Cancer (SCLC) Angiogenesis Drugs Targeting the Notch Pathway Outlook 275 References 275

8 13 Hedgehog Signaling Overview of Hedgehog Signaling Hedgehog Ligands The Primary Cilium Patched (Ptch) and Smoothened (Smo) Gli Transcription Factors Signaling in the Absence of Hedgehog Signaling after Binding of Hedgehog to Patched Activation of the Canonical Hedgehog Pathway in Basal Cell Carcinoma and Medulloblastoma Noncanonical Activation of Hedgehog-Responsive Genes KRas Atypical Protein Kinase-Lambda/Iota (apkci) PI3-Kinase-AKT (PI3K-AKT) mtor Paracrine Activation of Hedgehog Signaling Pharmacological Inhibition of the Hedgehog Pathway Inhibition of Hh Binding to Ptch Inhibitors of Smoothened Inhibition of Cilial Trafficking Inhibition of Gli Resistance against Direct Inhibitors of Smoothened Outlook 296 References TGFß Signaling The TGFß Superfamily Structure and Processing of TGFß Superfamily Members The TGFß Signaling Pathway Transcriptional Regulation by TGFß Superfamily Members Regulation of Stem Cells by TGFß Superfamily Members TGFß Superfamily Members as Tumor Suppressors in Human Cancer Active role of TGFß in Tumor Progression Drugs Interfering with TGFß Signaling TGFß Superfamily Members in Tumor Cachexia Outlook 315 Nomenclature 316 References 317 Index 319