Targeting Cell Survival Pathways to Enhance Response to Chemotherapy

Benjamin Bonavida

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128164327
• eBook ISBN: 9780128137543
• Topic: Medicine
• Subtopic: Biotechnology in Medicine

Targeting Cell Survival Pathways to Enhance Response to Chemotherapy encompasses recently developed molecular targeting agents and approaches that suppress cell survival signaling. Cell survival signaling attenuates the effectiveness of conventional chemotherapy and numerous mechanisms have been described, and continue to be described, which contribute to cell survival in the face of chemotherapy treatment.Key pathways leading to chemoresistance emanate from growth factor receptors, PI3K, STAT3, anti-apoptotic Bcl-2 family members, autophagy, and the DNA damage response pathway. New advances have underscored the potential of targeting each of these cell survival mechanisms to improve responsiveness to chemotherapy. This book reviews these recent advances and provides a foundational background and hints of new opportunities for basic, translational, and clinical investigators focused on improving therapeutic responses to chemotherapy.- Presents cutting-edge agents and approaches with proved success in different model systems that can be translated to a different type of cancer- Brings updated information to be used to propose new clinical trials investigating innovative strategies for improving responses to chemotherapy- Provides mechanistic details to help guide the design of laboratory studies associated with clinical trials

Chapter 1

Targeting Members of the Epidermal Growth Factor Receptor Family to Improve Response to Chemotherapy

Rachel A. O'Keefe

Jennifer R. Grandis

Daniel E. Johnson University of California at San Francisco, San Francisco, CA, United States

Abstract

Decades of research on the four receptor tyrosine kinases (RTKs) that comprise the human epidermal growth factor receptor (HER) family have established these proteins as key oncogenes in many cancer types. The strong evidence supporting pro-tumorigenic roles of HER3, HER4, and especially epidermal growth factor receptor (EGFR) and HER2 in cancer has led to the generation and use of HER family-targeted agents that can inhibit one or more of these RTKs. Although these inhibitors are used as a single agent in some contexts, they are often used in combination with chemotherapeutic agents and have been shown to enhance the response to chemotherapy in many cancer types. In this chapter, we outline the basic biology of the HER family receptors before examining each of the four receptors, focusing on mutations and other alterations that occur in cancer and on preclinical and clinical studies in which HER family-targeted agents were used to delay and/or overcome chemoresistance. Throughout, we address open questions in the field and discuss current and future areas of research.

Keywords

chemotherapy

EGFR

HER2

HER3

HER4

drug resistance

Abbreviations

ADCC Antibody-dependent cell-mediated cytotoxicity

AREG Amphiregulin

BTC Betacellulin

CDK Cyclin-dependent kinase

CDKN1A Cyclin-dependent kinase inhibitor p21Cip1

EGF Epidermal growth factor

EGFR Epidermal growth factor receptor

EPGN Epigen

Erα Estrogen receptorα

EREG Epiregulin

ERK Extracellular signal-regulated kinase

FDA Food and Drug Administration

HB-EGF Heparin-binding epidermal growth factor-like growth factor

HER Human epidermal growth factor receptor

HNSCC Head and neck squamous cell carcinoma

JAK Janus kinase

LCC Large cell carcinoma

LUAD Lung adenocarcinoma

LUSC Lung squamous cell carcinoma

MEK Mitogen-activated protein kinase kinase

mTOR Mechanistic target of rapamycin

NRG Neuregulin

NSCLC Non-small cell lung cancer

PI3K Phosphoinositide 3-kinase

PTEN Phosphatase and tensin homolog deleted on chromosome ten

RTK Receptor tyrosine kinase

STAT Signal transducer and activator of transcription

TACE Tumor necrosis factor-α converting enzyme

TGF-α Transforming growth factor-α

TKI Tyrosine kinase inhibitor

1.1. Introduction

For many years, the backbone of nonsurgical cancer treatment comprised chemotherapy and radiation. Although effective in some cases, many tumors proved refractory to these interventions, and low survival rates in many cancer types reflected the inadequacy of available cancer treatments. As signif...

Table of contents

• Cover
• Title page
• Table of Contents
• Copyright
• Dedication
• List of Contributors
• Author Biography
• Preface
• Chapter 1: Targeting Members of the Epidermal Growth Factor Receptor Family to Improve Response to Chemotherapy
• Chapter 2: Targeting the Hepatocyte Growth Factor Receptor to Overcome Resistance to Targeted Therapies
• Chapter 3: Roles for AXL and MERTK in Resistance to Cytotoxic and Targeted Therapies
• Chapter 4: The JNK Pathway in Drug Resistance
• Chapter 5: Fibroblast Growth Factor Receptor Inhibitors: Enhancing Therapeutic Strategies for Solid Tumors
• Chapter 6: PIK3CA mutations in colorectal and breast cancer: impact on oncogenesis and response to nonsteroidal anti-inflammatory drugs
• Chapter 7: STAT3 as a Major Contributor to Chemoresistance
• Chapter 8: Targeting the Hippo Pathway to Improve Response to Chemotherapy
• Chapter 9: Modulation of the Epigenome (Methylome) to Improve Chemotherapeutic Efficacy
• Chapter 10: Targeting the Ataxia Telangiectasia and Rad3 Signaling Pathway to Overcome Chemoresistance in Cancer
• Chapter 11: PARP Inhibition to Enhance Response to Chemotherapy
• Chapter 12: Autophagy Inhibition and Chemosensitization in Cancer Therapy
• Chapter 13: Targeting Necroptosis in Antitumor Therapy
• Index