Cancer Signaling, Enhanced Edition - From Molecular Biology to Targeted Therapy

Cover

Title Page

Copyright

Dedication

Contents

Preface

Acknowledgments

List of Abbreviations

About the Companion Website

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 of Therapeutic 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

References

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 to Therapy

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

References

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

References

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

References

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

References

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

References

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 in Wild-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 a Therapeutic 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

References

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

References

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 HIF1?????? and HIF2??????

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 HIF1?????? and the Warburg Effect

9.5.3.3 The Warburg Paradox

9.6 TCA Cycle Intermediates and Tumor Syndromes

9.7 Drugs Targeting HIFs

9.8 Outlook

References

Chapter 10 NF-??????B Pathways

10.1 NF-??????B Signaling in Inflammation, Growth Control, and Cancer

10.2 The Core of NF-??????B Signaling

10.3 Family of I??????B Proteins

10.4 Canonical NF-??????B Signaling from TNF Receptor 1

10.5 B-Cell Receptor Signaling

10.6 Other Receptors Activating the Canonical Pathway

10.7 Alternative NF-??????B Pathway

10.8 Terminating the NF-??????B Response

10.9 Ubiquitinylation in NF-??????B Signaling

10.10 Transcriptional Regulation

10.11 Physiological Role of NF-??????B Transcription Factors

10.12 Mutational Activation of NF-??????B Pathways in Malignant Disease

10.12.1 B-Cell Lymphomas

10.12.2 Multiple Myeloma

10.12.3 Activation of NF-??????B 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-??????B

10.14 Inflammation, NF-??????B, and Cancer

10.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases

10.16 Targeting NF-??????B Pathways

10.16.1 B-Cell Malignancies

10.16.2 Carcinomas

10.16.3 Anti-Inflammatory Drugs

10.17 Outlook

References

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 The Wnt Network

11.4 Proteins of the Wnt Pathway with Diverse Functions

11.4.1 APC (Adenomatous Polyposis Coli Protein)

11.4.2 ??????-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

References

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

References

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 (aPKC??????)

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

References

Chapter 14 TGF?????? Signaling

14.1 The TGF?????? Superfamily

14.2 Structure and Processing of TGF?????? Superfamily Members

14.3 The TGF?????? Signaling Pathway

14.4 Transcriptional Regulation by TGF?????? Superfamily Members

14.5 Regulation of Stem Cells by TGF?????? Superfamily Members

14.6 TGF?????? Superfamily Members as Tumor Suppressors in Human Cancer

14.7 Active role of TGF?????? in Tumor Progression

14.8 Drugs Interfering with TGF?????? Signaling

14.9 TGF?????? Superfamily Members in Tumor Cachexia

14.10 Outlook

Nomenclature

References

Index

EULA