Cancer Signaling: from molecular biology to targeted therapy

Content: 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 theWhole 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    References 21    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    References 44    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    References 61    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    References 95    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    References 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    References 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    References 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    References 180    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 TheWarburg Paradox 197    9.6 TCA Cycle Intermediates and Tumor Syndromes 200    9.7 Drugs Targeting HIFs 200    9.8 Outlook 202    References 203    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    References 234    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    References 255    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    References 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    References 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    References 317    Index 319