Cancer Signaling

Chapter 1: General Aspects of Signal Transduction and Cancer Therapy

• • 1.1 General Principles of Signal Transduction
• • 1.1.1 Biological Signals have to be Processed
• • 1.1.2 What is a Signal Transduction Pathway?
• • 1.1.3 Mechanisms of Direct Signal Transduction
• • 1.1.4 The Interactome Gives Insight into the Signaling Network
• • 1.1.5 Protein Domains for Protein–Protein Interaction and Signal Transduction
• • 1.1.6 Functions of Mutated Proteins in Tumor Cells
• • 1.2 Drugs against Cancer
• • 1.2.1 Terms and Definitions
• • 1.2.2 The Steps from a Normal Cell to a Tumor
• • 1.2.3 Interference Levels ofTherapeutic Drugs
• • 1.2.4 Drugs Attacking the Whole Cell
• • 1.2.4.1 DNA Alkylating Drugs
• • 1.2.5 Process-Blocking Drugs
• • 1.2.5.1 Drugs Blocking Synthesis of DNA and RNA
• • 1.2.5.2 Drugs Blocking the Synthesis of DNA and RNA Precursor Molecules
• • 1.2.5.3 Drugs Blocking Dynamics of Microtubules
• • 1.2.6 Innovative Molecule-Interfering Drugs
• • 1.2.7 Fast-Dividing Normal Cells and Slowly Dividing Tumor Cells: Side Effects and Relapse
• • 1.2.8 Drug Resistance
• • 1.2.8.1 Drugs Circumventing Resistance
• • 1.3 Outlook

Chapter 2: Tumor Cell Heterogeneity and Resistance to Targeted Therapy

• • 2.1 The Genetic Basis of Tumorigenesis
• • 2.2 Clonal Heterogeneity
• • 2.2.1 Clonal Origin of Tumors
• • 2.2.2 Clonal Evolution
• • 2.2.3 The Time Course of Clonal Evolution
• • 2.2.4 Clonal Evolution and Resistance toTherapy
• • 2.2.5 Targeting Essential Drivers (Driver Addiction)
• • 2.2.6 Resistance by Alternative Pathway Activation
• • 2.2.7 Overcoming Resistance by Combinatorial Therapies
• • 2.3 Tumor Stem Cells and Tumor Cell Hierarchies
• • 2.4 Epigenetics and Phenotypic Plasticity
• • 2.5 Microenvironment
• • 2.6 Outlook

Chapter 3: Cell Cycle of Tumor Cells

• • 3.1 Properties of Tumor Cells
• • 3.1.1 Differences between Tumor Cells and Normal Cells In vitro
• • 3.1.2 Regulation of Cell Number
• • 3.2 The Cell Cycle
• • 3.2.1 Checkpoints
• • 3.2.2 Cyclins
• • 3.2.3 Cyclin-Dependent Kinases (CDKs)
• • 3.2.4 The Retinoblastoma-Associated Protein Rb as Regulator of the Cell Cycle
• • 3.2.5 Inhibitors of CDKs
• • 3.2.6 Checkpoints and DNA Integrity
• • 3.2.7 The Repair Mechanism Depends on the Cell Cycle Phase
• • 3.2.8 Tumor-Relevant Proteins in the Cell Cycle
• • 3.3 The Cell Cycle as Therapeutic Target
• • 3.3.1 Small Compounds Inhibiting Cell-Cycle-Dependent Kinases as Anticancer Drugs
• • 3.4 Outlook

Chapter 4: Cell Aging and Cell Death

• • 4.1 A Cell’s Journey through Life
• • 4.2 Cellular Aging and Senescence
• • 4.2.1 Replicative Senescence
• • 4.2.2 Shortening of Chromosomal Telomeres during Replication
• • 4.2.3 Chromosomal Telomeres
• • 4.2.4 Telomerase
• • 4.2.5 Animal Models
• • 4.2.6 Overcoming Replicative Senescence in Tumor Cells
• • 4.2.7 Nonreplicative Senescence
• • 4.3 Cell Death
• • 4.4 Morphologies of Dying Cells
• • 4.4.1 Morphology of Necrotic Cells
• • 4.4.2 Morphologies of Apoptotic and Necroptotic Cells
• • 4.4.3 Morphology of Autophagy
• • 4.5 Necroptosis
• • 4.6 Apoptosis in the Healthy Organism
• • 4.6.1 The Four Phases of Apoptosis
• • 4.6.2 Extrinsic Initiation
• • 4.6.2.1 TNF Pathway
• • 4.6.2.2 TNF Receptor Downstream Signaling
• • 4.6.2.3 Caspases
• • 4.6.3 Intrinsic Initiation
• • 4.6.4 Execution Phase
• • 4.6.5 Phagocytosis and Degradation
• • 4.7 Apoptosis of Tumor Cells
• • 4.8 Autophagy
• • 4.8.1 Autophagy in Tumor Development
• • 4.8.2 Regulation of Autophagy
• • 4.9 Cell Death and Cell Aging as Therapeutic Targets in Cancer Treatment
• • 4.9.1 Induction of Apoptosis by Radiation
• • 4.9.2 Induction of Apoptosis by Conventional Anticancer Drugs
• • 4.9.3 Innovative Drugs Targeting Aging and Death Pathways
• • 4.9.3.1 Targeting TRAIL (TNF-Related Apoptosis-Inducing Ligand)
• • 4.9.3.2 Targeting Bcl-2
• • 4.9.3.3 Simulating the Effects of cIAP Inhibitors
• • 4.9.3.4 Targeting Autophagy Pathways
• • 4.10 Senescence in Anticancer Therapy
• • 4.11 Outlook

Chapter 5: Growth Factors and Receptor Tyrosine Kinases

• • 5.1 Growth Factors
• • 5.2 Protein Kinases
• • 5.2.1 Receptor Protein Tyrosine Kinases
• • 5.2.2 Receptor Protein Tyrosine Kinase Activation
• • 5.2.3 The Family of EGF Receptors
• • 5.2.4 The Family of PDGF Receptors
• • 5.2.5 The Insulin Receptor Family and its Ligands
• • 5.2.5.1 Prostate-Specific Antigen
• • 5.2.6 Signaling from Receptor Protein Tyrosine Kinases
• • 5.2.7 Association of PDGF and EGF Receptors with Cytoplasmic Proteins
• • 5.2.7.1 Signaling from PDGF and EGF Receptors
• • 5.2.8 Constitutive Activation of RTKs in Tumor Cells
• • 5.3 Therapy of Tumors with Dysregulated Growth Factors and their Receptors
• • 5.3.1 Targeting Growth Factors
• • 5.3.2 Targeting EGF Receptors by Antibodies
• • 5.3.3 Targeting EGF Receptors by Kinase Inhibitors
• • 5.4 Outlook

Chapter 6: The Philadelphia Chromosome and BCR-ABL1

• • 6.1 Analysis of Chromosomes
• • 6.2 Aberrant Chromosomes in Tumor Cells
• • 6.3 The Philadelphia Chromosome
• • 6.3.1 Molecular Diagnosis of the BCR-ABL1 Fusion Gene
• • 6.4 The BCR-ABL1 Kinase Protein
• • 6.4.1 Structural Aspects of BCR-ABL1 Kinase
• • 6.4.2 Substrates and Effects of BCR-ABL1 Kinase
• • 6.4.3 The BCR-ABL1 Kinase Inhibitor Imatinib
• • 6.4.4 Imatinib in Treatment of Tumors Other than CML
• • 6.4.5 Mechanism of Imatinib Action
• • 6.4.6 Resistance against Imatinib
• • 6.4.7 BCR-ABL1 Kinase Inhibitors of the Second and the Third Generation
• • 6.4.8 Allosteric Inhibitors of BCR-ABL1
• • 6.5 Outlook

Chapter 7: MAPK Signaling

• • 7.1 The RAS Gene
• • 7.2 The Ras Protein
• • 7.2.1 The Ras Protein as a Molecular Switch
• • 7.2.2 The GTPase Reaction inWild-Type and Mutant Ras Proteins
• • 7.3 Neurofibromin: The Second RasGAP
• • 7.4 Downstream Signaling of Ras
• • 7.4.1 The BRaf Protein
• • 7.4.2 The BRAF Gene
• • 7.4.3 The MAPK Signaling Pathway
• • 7.4.4 Mutations in Genes of the MAPK Pathway
• • 7.5 Therapy of Tumors with Constitutively Active MAPK Pathway
• • 7.5.1 Ras as aTherapeutic Target
• • 7.5.1.1 Inhibiting Posttranslational Modification and Membrane Anchoring of Ras
• • 7.5.1.2 Direct Targeting Mutant Ras
• • 7.5.1.3 Preventing Ras/Raf Interaction
• • 7.5.2 BRaf Inhibitors
• • 7.5.2.1 Consequences of BRaf Inhibition by Vemurafenib
• • 7.5.2.2 Resistance against BRaf Inhibitors Based on BRaf Dependent Mechanisms
• • 7.5.2.3 Resistance against BRaf Inhibitors Based on BRaf Independent Mechanisms
• • 7.5.2.4 Treatment of Vemurafenib-Resistant Tumors
• • 7.6 Outlook

Chapter 8: PI3K-AKT-mTOR Signaling

• • 8.1 Discovery of the PI3K-AKT-mTOR Pathway
• • 8.2 Phosphatidylinositol-3-Kinase (PI3K)
• • 8.3 Inositol Trisphosphate, Diacylglycerol, and Protein Kinase C (PKC)
• • 8.3.1 Protein Kinase C (PKC)
• • 8.3.2 Activation and Functions of PKC
• • 8.4 AKT (Protein Kinase B)
• • 8.5 mTOR
• • 8.5.1 mTORC1: Inputs
• • 8.5.2 mTORC2: Inputs
• • 8.5.3 mTORC1: Outputs
• • 8.5.4 mTORC2: Outputs
• • 8.5.5 Feedback Controls
• • 8.6 PTEN
• • 8.7 Activation of the PI3K/AKT/mTOR Pathway in Cancer
• • 8.7.1 Sporadic Carcinomas
• • 8.7.2 Hamartoma Syndromes
• • 8.8 PKC in Cancer
• • 8.9 Therapy
• • 8.10 Outlook

Chapter 9: Hypoxia-Inducible Factor (HIF)

• • 9.1 Responses of HIF to Hypoxia and Oncogenic Pathways
• • 9.2 HIF Functional Domains
• • 9.3 Regulation of HIF
• • 9.3.1 Regulation of HIF under Normoxic Conditions
• • 9.3.2 Regulation of HIF under Hypoxic Conditions
• • 9.3.3 Oxygen-Independent Regulation of HIF
• • 9.3.4 Context-Dependence of HIF Regulation
• • 9.4 Regulation of HIF in Malignant Disease
• • 9.4.1 Expression of HIF in Human Tumors
• • 9.4.2 von Hippel–Lindau Disease
• • 9.5 HIF Targets in Cancer
• • 9.5.1 Target Genes of HIF1α and HIF2α
• • 9.5.2 HIF Target Genes Affecting Tumor Growth
• • 9.5.3 HIF Target Genes Affecting Metabolism
• • 9.5.3.1 Glucose Uptake and Metabolism
• • 9.5.3.2 HIF1α and theWarburg Effect
• • 9.5.3.3 The Warburg Paradox
• • 9.6 TCA Cycle Intermediates and Tumor Syndromes
• • 9.7 Drugs Targeting HIFs
• • 9.8 Outlook

Chapter 10: NF-κB Pathways

• • 10.1 NF-κB Signaling in Inflammation, Growth Control, and Cancer
• • 10.2 The Core of NF-κB Signaling
• • 10.3 Family of IκB Proteins
• • 10.4 Canonical NF-κB Signaling from TNF Receptor 1
• • 10.5 B-Cell Receptor Signaling
• • 10.6 Other Receptors Activating the Canonical Pathway
• • 10.7 Alternative NF-κB Pathway
• • 10.8 Terminating the NF-κB Response
• • 10.9 Ubiquitinylation in NF-κB Signaling
• • 10.10 Transcriptional Regulation
• • 10.11 Physiological Role of NF-κB Transcription Factors
• • 10.12 Mutational Activation of NF-κB Pathways in Malignant Disease
• • 10.12.1 B-Cell Lymphomas
• • 10.12.2 Multiple Myeloma
• • 10.12.3 Activation of NF-κB Pathways by Polycomb-Mediated Loss of microRNA-31 in Adult T-Cell Leukemia/Lymphoma
• • 10.12.4 Carcinomas
• • 10.13 Cross Talk between Mutant KRas and NF-κB
• • 10.14 Inflammation, NF-κB, and Cancer
• • 10.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases
• • 10.16 Targeting NF-κB Pathways
• • 10.16.1 B-Cell Malignancies
• • 10.16.2 Carcinomas
• • 10.16.3 Anti-Inflammatory Drugs
• • 10.17 Outlook

Chapter 11: Wnt Signaling

• • 11.1 The History of Wnt
• • 11.2 The Canonical Wnt Pathway
• • 11.2.1 The Nonactivated Wnt Pathway
• • 11.2.2 The Physiologically Activated Wnt Pathway
• • 11.2.3 The Nonphysiologically Activated Wnt Pathway in the Absence of the Wnt Signal
• • 11.3 TheWnt Network
• • 11.4 Proteins of the Wnt Pathway with Diverse Functions
• • 11.4.1 APC (Adenomatous Polyposis Coli Protein)
• • 11.4.2 β-Catenin
• • 11.4.3 Axin
• • 11.5 The Wnt Targetome
• • 11.5.1 The Three Levels of the Wnt Targetome
• • 11.5.2 Biological Effects of Wnt Target Genes
• • 11.6 The Wnt Pathway as Therapeutic Target
• • 11.6.1 Strategies to Identify Anti-Wnt Drugs
• • 11.6.2 Molecules Interfering with the Wnt Pathway
• • 11.7 Outlook

Chapter 12: Notch Signaling

• • 12.1 Introduction
• • 12.2 Determination of Cell Fate Decisions
• • 12.3 Notch Proteins and Notch Ligands
• • 12.4 Notch Signaling
• • 12.4.1 The Notch Signaling Pathway
• • 12.4.2 Regulation of Notch Signaling by Posttranslational Modification
• • 12.4.2.1 Ubiquitinylation
• • 12.4.2.2 Glycosylation of Notch
• • 12.5 Notch Signaling in Malignant Disease
• • 12.5.1 Acute T-Cell Leukemia (T-ALL)
• • 12.5.2 Chronic Lymphocytic Leukemia
• • 12.5.3 Chronic Myelomonocytic Leukemia (CMML)
• • 12.5.4 Breast Cancer
• • 12.5.5 Cholangiocellular Carcinoma (CCC)
• • 12.5.6 Squamous Cell Carcinomas (SCCs)
• • 12.5.7 Small-Cell Lung Cancer (SCLC)
• • 12.5.8 Angiogenesis
• • 12.6 Drugs Targeting the Notch Pathway
• • 12.7 Outlook

Chapter 13: Hedgehog Signaling

• • 13.1 Overview of Hedgehog Signaling
• • 13.2 Hedgehog Ligands
• • 13.3 The Primary Cilium
• • 13.4 Patched (Ptch) and Smoothened (Smo)
• • 13.5 Gli Transcription Factors
• • 13.6 Signaling in the Absence of Hedgehog
• • 13.7 Signaling after Binding of Hedgehog to Patched
• • 13.8 Activation of the Canonical Hedgehog Pathway in Basal Cell Carcinoma and Medulloblastoma
• • 13.9 Noncanonical Activation of Hedgehog-Responsive Genes
• • 13.9.1 KRas
• • 13.9.2 Atypical Protein Kinase-Lambda/Iota (aPKCι)
• • 13.9.3 PI3-Kinase-AKT (PI3K-AKT)
• • 13.9.4 mTOR
• • 13.10 Paracrine Activation of Hedgehog Signaling
• • 13.11 Pharmacological Inhibition of the Hedgehog Pathway
• • 13.11.1 Inhibition of Hh Binding to Ptch
• • 13.11.2 Inhibitors of Smoothened
• • 13.11.3 Inhibition of Cilial Trafficking
• • 13.11.4 Inhibition of Gli
• • 13.11.5 Resistance against Direct Inhibitors of Smoothened
• • 13.12 Outlook

Chapter 14: TGFβ Signaling

• • 14.1 The TGFβ Superfamily
• • 14.2 Structure and Processing of TGFβ Superfamily Members
• • 14.3 The TGFβ Signaling Pathway
• • 14.4 Transcriptional Regulation by TGFβ Superfamily Members
• • 14.5 Regulation of Stem Cells by TGFβ Superfamily Members
• • 14.6 TGFβ Superfamily Members as Tumor Suppressors in Human Cancer
• • 14.7 Active role of TGFβ in Tumor Progression
• • 14.8 Drugs Interfering with TGFβ Signaling
• • 14.9 TGF β Superfamily Members in Tumor Cachexia
• • 14.10 Outlook