Main description:

Cancer, which has become the second-most prevalent health issue globally, is essentially a malfunction of cell signaling. Understanding how the intricate signaling networks of cells and tissues allow cancer to thrive - and how they can be turned into potent weapons against it - is the key to managing cancer in the clinic and improving the outcome of cancer therapies. In their ground-breaking textbook, the authors provide a compelling story of how cancer works on the molecular level, and how targeted therapies using kinase inhibitors and other modulators of signaling pathways can contain and eventually cure it. The first part of the book gives an introduction into the cell and molecular biology of cancer, focusing on the key mechanisms of cancer formation. The second part of the book introduces the main signaling transduction mechanisms responsible for carcinogenesis and compares their function in healthy versus cancer cells. In contrast to the complexity of its topic, the text is easy to read. 32 specially prepared teaching videos on key concepts and pathways in cancer signaling are available online.

Contents:

Preface XV Acknowledgments XXI List of Abbreviations XXIII About the Companion Website XXIX 1 General Aspects of Signal Transduction and Cancer Therapy 1 1.1 General Principles of Signal Transduction 2 1.1.1 Biological Signals have to be Processed 2 1.1.2 What is a Signal Transduction Pathway? 2 1.1.3 Mechanisms of Direct Signal Transduction 4 1.1.4 The Interactome Gives Insight into the Signaling Network 5 1.1.5 Protein Domains for Protein Protein Interaction and Signal Transduction 6 1.1.6 Functions of Mutated Proteins in Tumor Cells 8 1.2 Drugs against Cancer 10 1.2.1 Terms and Definitions 10 1.2.2 The Steps from a Normal Cell to a Tumor 10 1.2.3 Interference Levels ofTherapeutic Drugs 11 1.2.4 Drugs Attacking the Whole Cell 12 1.2.4.1 DNA Alkylating Drugs 13 1.2.5 Process-Blocking Drugs 14 1.2.5.1 Drugs Blocking Synthesis of DNA and RNA 14 1.2.5.2 Drugs Blocking the Synthesis of DNA and RNA Precursor Molecules 15 1.2.5.3 Drugs Blocking Dynamics of Microtubules 16 1.2.6 Innovative Molecule-Interfering Drugs 18 1.2.7 Fast-Dividing Normal Cells and Slowly Dividing Tumor Cells: Side Effects and Relapse 19 1.2.8 Drug Resistance 19 1.2.8.1 Drugs Circumventing Resistance 19 1.3 Outlook 20 2 Tumor Cell Heterogeneity and Resistance to Targeted Therapy 23 2.1 The Genetic Basis of Tumorigenesis 24 2.2 Clonal Heterogeneity 24 2.2.1 Clonal Origin of Tumors 24 2.2.2 Clonal Evolution 26 2.2.3 The Time Course of Clonal Evolution 30 2.2.4 Clonal Evolution and Resistance toTherapy 32 2.2.5 Targeting Essential Drivers (Driver Addiction) 34 2.2.6 Resistance by Alternative Pathway Activation 36 2.2.7 Overcoming Resistance by Combinatorial Therapies 36 2.3 Tumor Stem Cells and Tumor Cell Hierarchies 37 2.4 Epigenetics and Phenotypic Plasticity 40 2.5 Microenvironment 42 2.6 Outlook 43 3 Cell Cycle of Tumor Cells 47 3.1 Properties of Tumor Cells 48 3.1.1 Differences between Tumor Cells and Normal Cells In vitro 49 3.1.2 Regulation of Cell Number 49 3.2 The Cell Cycle 50 3.2.1 Checkpoints 51 3.2.2 Cyclins 52 3.2.3 Cyclin-Dependent Kinases (CDKs) 53 3.2.4 The Retinoblastoma-Associated Protein Rb as Regulator of the Cell Cycle 54 3.2.5 Inhibitors of CDKs 54 3.2.6 Checkpoints and DNA Integrity 55 3.2.7 The Repair Mechanism Depends on the Cell Cycle Phase 57 3.2.8 Tumor-Relevant Proteins in the Cell Cycle 57 3.3 The Cell Cycle as Therapeutic Target 58 3.3.1 Small Compounds Inhibiting Cell-Cycle-Dependent Kinases as Anticancer Drugs 59 3.4 Outlook 60 4 Cell Aging and Cell Death 63 4.1 A Cell s Journey through Life 64 4.2 Cellular Aging and Senescence 64 4.2.1 Replicative Senescence 65 4.2.2 Shortening of Chromosomal Telomeres during Replication 67 4.2.3 Chromosomal Telomeres 67 4.2.4 Telomerase 69 4.2.5 Animal Models 72 4.2.6 Overcoming Replicative Senescence in Tumor Cells 72 4.2.7 Nonreplicative Senescence 73 4.3 Cell Death 74 4.4 Morphologies of Dying Cells 75 4.4.1 Morphology of Necrotic Cells 75 4.4.2 Morphologies of Apoptotic and Necroptotic Cells 75 4.4.3 Morphology of Autophagy 76 4.5 Necroptosis 76 4.6 Apoptosis in the Healthy Organism 79 4.6.1 The Four Phases of Apoptosis 80 4.6.2 Extrinsic Initiation 81 4.6.2.1 TNF Pathway 81 4.6.2.2 TNF Receptor Downstream Signaling 82 4.6.2.3 Caspases 82 4.6.3 Intrinsic Initiation 83 4.6.4 Execution Phase 84 4.6.5 Phagocytosis and Degradation 85 4.7 Apoptosis of Tumor Cells 85 4.8 Autophagy 86 4.8.1 Autophagy in Tumor Development 87 4.8.2 Regulation of Autophagy 89 4.9 Cell Death and Cell Aging as Therapeutic Targets in Cancer Treatment 89 4.9.1 Induction of Apoptosis by Radiation 89 4.9.2 Induction of Apoptosis by Conventional Anticancer Drugs 90 4.9.3 Innovative Drugs Targeting Aging and Death Pathways 92 4.9.3.1 Targeting TRAIL (TNF-Related Apoptosis-Inducing Ligand) 92 4.9.3.2 Targeting Bcl-2 92 4.9.3.3 Simulating the Effects of cIAP Inhibitors 92 4.9.3.4 Targeting Autophagy Pathways 93 4.10 Senescence in Anticancer Therapy 93 4.11 Outlook 94 5 Growth Factors and Receptor Tyrosine Kinases 97 5.1 Growth Factors 98 5.2 Protein Kinases 98 5.2.1 Receptor Protein Tyrosine Kinases 100 5.2.2 Receptor Protein Tyrosine Kinase Activation 102 5.2.3 The Family of EGF Receptors 103 5.2.4 The Family of PDGF Receptors 104 5.2.5 The Insulin Receptor Family and its Ligands 107 5.2.5.1 Prostate-Specific Antigen 107 5.2.6 Signaling from Receptor Protein Tyrosine Kinases 108 5.2.7 Association of PDGF and EGF Receptors with Cytoplasmic Proteins 109 5.2.7.1 Signaling from PDGF and EGF Receptors 112 5.2.8 Constitutive Activation of RTKs in Tumor Cells 113 5.3 Therapy of Tumors with Dysregulated Growth Factors and their Receptors 115 5.3.1 Targeting Growth Factors 115 5.3.2 Targeting EGF Receptors by Antibodies 116 5.3.3 Targeting EGF Receptors by Kinase Inhibitors 117 5.4 Outlook 117 6 The Philadelphia Chromosome and BCR-ABL1 119 6.1 Analysis of Chromosomes 120 6.2 Aberrant Chromosomes in Tumor Cells 121 6.3 The Philadelphia Chromosome 122 6.3.1 Molecular Diagnosis of the BCR-ABL1 Fusion Gene 125 6.4 The BCR-ABL1 Kinase Protein 125 6.4.1 Structural Aspects of BCR-ABL1 Kinase 126 6.4.2 Substrates and Effects of BCR-ABL1 Kinase 128 6.4.3 The BCR-ABL1 Kinase Inhibitor Imatinib 129 6.4.4 Imatinib in Treatment of Tumors Other than CML 130 6.4.5 Mechanism of Imatinib Action 130 6.4.6 Resistance against Imatinib 130 6.4.7 BCR-ABL1 Kinase Inhibitors of the Second and the Third Generation 131 6.4.8 Allosteric Inhibitors of BCR-ABL1 132 6.5 Outlook 133 7 MAPK Signaling 135 7.1 The RAS Gene 136 7.2 The Ras Protein 136 7.2.1 The Ras Protein as a Molecular Switch 138 7.2.2 The GTPase Reaction inWild-Type and Mutant Ras Proteins 139 7.3 Neurofibromin: The Second RasGAP 143 7.4 Downstream Signaling of Ras 144 7.4.1 The BRaf Protein 145 7.4.2 The BRAF Gene 147 7.4.3 The MAPK Signaling Pathway 147 7.4.4 Mutations in Genes of the MAPK Pathway 148 7.5 Therapy of Tumors with Constitutively Active MAPK Pathway 149 7.5.1 Ras as aTherapeutic Target 150 7.5.1.1 Inhibiting Posttranslational Modification and Membrane Anchoring of Ras 150 7.5.1.2 Direct Targeting Mutant Ras 152 7.5.1.3 Preventing Ras/Raf Interaction 152 7.5.2 BRaf Inhibitors 152 7.5.2.1 Consequences of BRaf Inhibition by Vemurafenib 154 7.5.2.2 Resistance against BRaf Inhibitors Based on BRaf Dependent Mechanisms 154 7.5.2.3 Resistance against BRaf Inhibitors Based on BRaf Independent Mechanisms 155 7.5.2.4 Treatment of Vemurafenib-Resistant Tumors 155 7.6 Outlook 156 8 PI3K-AKT-mTOR Signaling 159 8.1 Discovery of the PI3K-AKT-mTOR Pathway 160 8.2 Phosphatidylinositol-3-Kinase (PI3K) 161 8.3 Inositol Trisphosphate, Diacylglycerol, and Protein Kinase C (PKC) 163 8.3.1 Protein Kinase C (PKC) 163 8.3.2 Activation and Functions of PKC 165 8.4 AKT (Protein Kinase B) 165 8.5 mTOR 168 8.5.1 mTORC1: Inputs 170 8.5.2 mTORC2: Inputs 171 8.5.3 mTORC1: Outputs 171 8.5.4 mTORC2: Outputs 172 8.5.5 Feedback Controls 172 8.6 PTEN 172 8.7 Activation of the PI3K/AKT/mTOR Pathway in Cancer 173 8.7.1 Sporadic Carcinomas 173 8.7.2 Hamartoma Syndromes 174 8.8 PKC in Cancer 175 8.9 Therapy 176 8.10 Outlook 178 9 Hypoxia-Inducible Factor (HIF) 183 9.1 Responses of HIF to Hypoxia and Oncogenic Pathways 184 9.2 HIF Functional Domains 185 9.3 Regulation of HIF 186 9.3.1 Regulation of HIF under Normoxic Conditions 186 9.3.2 Regulation of HIF under Hypoxic Conditions 189 9.3.3 Oxygen-Independent Regulation of HIF 189 9.3.4 Context-Dependence of HIF Regulation 190 9.4 Regulation of HIF in Malignant Disease 191 9.4.1 Expression of HIF in Human Tumors 191 9.4.2 von Hippel Lindau Disease 191 9.5 HIF Targets in Cancer 192 9.5.1 Target Genes of HIF1 and HIF2 192 9.5.2 HIF Target Genes Affecting Tumor Growth 193 9.5.3 HIF Target Genes Affecting Metabolism 195 9.5.3.1 Glucose Uptake and Metabolism 195 9.5.3.2 HIF1 and theWarburg Effect 197 9.5.3.3 The Warburg Paradox 197 9.6 TCA Cycle Intermediates and Tumor Syndromes 200 9.7 Drugs Targeting HIFs 200 9.8 Outlook 202 10 NF- B Pathways 205 10.1 NF- B Signaling in Inflammation, Growth Control, and Cancer 206 10.2 The Core of NF- B Signaling 207 10.3 Family of I B Proteins 209 10.4 Canonical NF- B Signaling from TNF Receptor 1 210 10.5 B-Cell Receptor Signaling 213 10.6 Other Receptors Activating the Canonical Pathway 214 10.7 Alternative NF- B Pathway 214 10.8 Terminating the NF- B Response 215 10.9 Ubiquitinylation in NF- B Signaling 217 10.10 Transcriptional Regulation 219 10.11 Physiological Role of NF- B Transcription Factors 221 10.12 Mutational Activation of NF- B Pathways in Malignant Disease 222 10.12.1 B-Cell Lymphomas 222 10.12.2 Multiple Myeloma 223 10.12.3 Activation of NF- B Pathways by Polycomb-Mediated Loss of microRNA-31 in Adult T-Cell Leukemia/Lymphoma 225 10.12.4 Carcinomas 227 10.13 Cross Talk between Mutant KRas and NF- B 227 10.14 Inflammation, NF- B, and Cancer 228 10.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases 230 10.16 Targeting NF- B Pathways 232 10.16.1 B-Cell Malignancies 232 10.16.2 Carcinomas 233 10.16.3 Anti-Inflammatory Drugs 233 10.17 Outlook 233 11 Wnt Signaling 237 11.1 The History of Wnt 238 11.2 The Canonical Wnt Pathway 238 11.2.1 The Nonactivated Wnt Pathway 239 11.2.2 The Physiologically Activated Wnt Pathway 241 11.2.3 The Nonphysiologically Activated Wnt Pathway in the Absence of the Wnt Signal 242 11.3 TheWnt Network 243 11.4 Proteins of the Wnt Pathway with Diverse Functions 243 11.4.1 APC (Adenomatous Polyposis Coli Protein) 243 11.4.2 -Catenin 245 11.4.3 Axin 245 11.5 The Wnt Targetome 246 11.5.1 The Three Levels of the Wnt Targetome 247 11.5.2 Biological Effects of Wnt Target Genes 248 11.6 The Wnt Pathway as Therapeutic Target 250 11.6.1 Strategies to Identify Anti-Wnt Drugs 250 11.6.2 Molecules Interfering with the Wnt Pathway 253 11.7 Outlook 254 12 Notch Signaling 257 12.1 Introduction 258 12.2 Determination of Cell Fate Decisions 258 12.3 Notch Proteins and Notch Ligands 259 12.4 Notch Signaling 261 12.4.1 The Notch Signaling Pathway 261 12.4.2 Regulation of Notch Signaling by Posttranslational Modification 264 12.4.2.1 Ubiquitinylation 264 12.4.2.2 Glycosylation of Notch 265 12.5 Notch Signaling in Malignant Disease 266 12.5.1 Acute T-Cell Leukemia (T-ALL) 266 12.5.2 Chronic Lymphocytic Leukemia 268 12.5.3 Chronic Myelomonocytic Leukemia (CMML) 269 12.5.4 Breast Cancer 269 12.5.5 Cholangiocellular Carcinoma (CCC) 270 12.5.6 Squamous Cell Carcinomas (SCCs) 271 12.5.7 Small-Cell Lung Cancer (SCLC) 272 12.5.8 Angiogenesis 272 12.6 Drugs Targeting the Notch Pathway 273 12.7 Outlook 275 13 Hedgehog Signaling 277 13.1 Overview of Hedgehog Signaling 278 13.2 Hedgehog Ligands 279 13.3 The Primary Cilium 280 13.4 Patched (Ptch) and Smoothened (Smo) 283 13.5 Gli Transcription Factors 283 13.6 Signaling in the Absence of Hedgehog 284 13.7 Signaling after Binding of Hedgehog to Patched 284 13.8 Activation of the Canonical Hedgehog Pathway in Basal Cell Carcinoma and Medulloblastoma 285 13.9 Noncanonical Activation of Hedgehog-Responsive Genes 288 13.9.1 KRas 288 13.9.2 Atypical Protein Kinase-Lambda/Iota (aPKC ) 288 13.9.3 PI3-Kinase-AKT (PI3K-AKT) 289 13.9.4 mTOR 290 13.10 Paracrine Activation of Hedgehog Signaling 291 13.11 Pharmacological Inhibition of the Hedgehog Pathway 292 13.11.1 Inhibition of Hh Binding to Ptch 293 13.11.2 Inhibitors of Smoothened 293 13.11.3 Inhibition of Cilial Trafficking 294 13.11.4 Inhibition of Gli 294 13.11.5 Resistance against Direct Inhibitors of Smoothened 295 13.12 Outlook 296 14 TGF Signaling 299 14.1 The TGF Superfamily 300 14.2 Structure and Processing of TGF Superfamily Members 301 14.3 The TGF Signaling Pathway 302 14.4 Transcriptional Regulation by TGF Superfamily Members 305 14.5 Regulation of Stem Cells by TGF Superfamily Members 307 14.6 TGF Superfamily Members as Tumor Suppressors in Human Cancer 309 14.7 Active role of TGF in Tumor Progression 310 14.8 Drugs Interfering with TGF Signaling 312 14.9 TGF Superfamily Members in Tumor Cachexia 313 14.10 Outlook 315 Nomenclature 316 Index 319