Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy

Benjamin Bonavida

• Verlag: Academic Press
• Jahr: 2018
• ISBN:
  9780128127384
• Thema: Medicina
• Thema: Biotecnología en medicina

Tyrosine Kinase Inhibitors as Sensitizing Agents for Chemotherapy, the fourth volume in the Cancer Sensitizing Agents for Chemotherapy Series, focuses on strategic combination therapies that involve a variety of tyrosine kinase inhibitors working together to overcome multi-drug resistance in cancer cells. The book discusses several tyrosine kinase inhibitors that have been used as sensitizing agents, such as EGFR, BCR-ABL, ALK and BRAF. In each chapter, readers will find comprehensive knowledge on the inhibitor and its action, including its biochemical, genetic, and molecular mechanisms' emphases. This book is a valuable source for oncologists, cancer researchers and those interested in applying new sensitizing agents to their research in clinical practice and in trials.

• Summarizes the sensitizing role of some tyrosine kinase inhibitors in existing research
• Brings recent findings in several cancer types, both experimental and clinically, with a particular emphases on underlying biochemical, genetic, and molecular mechanisms
• Provides an updated and comprehensive knowledge regarding the field of combinational cancer treatment

Chapter 1

EGFR and HER2 Inhibitors as Sensitizing Agents for Cancer Chemotherapy

Anna Maria Barbuti; Guan-Nan Zhang; Pranav Gupta; Silpa Narayanan; Zhe-Sheng Chen Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States

Abstract

Traditional chemotherapy drugs aim to fight cancer cell proliferation, targeting DNA or mechanisms of mitosis. Unfortunately, some chemotherapy drugs fail due to innate or acquired drug resistance. Clinical cancer therapy regimens employ multiple drugs to prevent chemoresistance and limit adverse effects for the patient.

One significant reason for chemoresistance is an increased drug efflux, primarily caused by the presence (or overexpression) of ATP-binding cassette (ABC) transporters across the cell membrane which “pump out” the chemotherapy drug. Several classic chemotherapies including doxorubicin (adriamycin), paclitaxel, topotecan, and mitoxantrone are known substrates of certain subclasses of ABC transporters. This presents a problem for the efficacy of the anticancer treatment if the tumor develops overexpression of these transporters as a mechanism of resistance.

The epidermal growth factor receptor (EGFR) family and the human EGFR 2 (HER2) of the receptor tyrosine kinases play essential roles in regulating cell proliferation, survival, and differentiation. Because of their pivotal role in cellular function and growth, many inhibitors of EGFR and HER2 have been approved as targeted treatments for many diseases and cancers. Many of these inhibitors also play an interesting role in cancer therapy as they have been found to sensitize chemoresistant tumors and rescue cancer cells those have stopped responding to chemotherapy treatments. This chapter will explore the EGFR and HER2 inhibitors gefitinib, erlotinib, lapatinib, afatinib, pelitinib, and osimertinib as promising clinical tools in sensitizing chemoresistant tumors.

Keywords

ABC transporters; Chemotherapy; Chemoresistance; EGFR; HER2; Tyrosine kinase inhibitors

Abbreviations

ABC ATP-binding cassette

ATP adenosine triphosphate

Bcl B-cell lymphoma

DNA deoxyribonucleic acid

EGFR epidermal growth factor receptor

FDA Food and Drug Administration

HER2 human EGFR 2

MDR multidrug resistance

Met methionine

NSCLC nonsmall-cell lung cancer

TKI tyrosine kinase inhibitor

Tyr tyrosine

Acknowledgments

We would like to thank the editors and reviewers of this work. We especially thank Dr. Don Yang for her direction and the opportunity to write this book chapter. We would also like to thank the Pharmaceutical Sciences Department at St. John's University for their educational support.

Conflict of Interest

No potential conflicts of interest were disclosed.

Introduction

Tyrosine Kinases: Targeting the EGFR and HER2 Receptors

Kinases are enzymes which catalyze the transfer of a phosphate group from a high-energy phosphate-contacting molecule (such as ATP) to an acceptor molecule. Tyrosine kinases are a subclass of kinase proteins, where the phosphorylation is directed to the tyrosine residue of the acceptor protein [1].

The epidermal growth factor receptor (EGFR) family of the receptor tyrosine kinases plays essential roles in regulating cell proliferation, survival, and differentiation. The human EGFR (HER) family consists of four members that belong to the ErbB lineage of proteins, EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. The ErbB receptors carry out many functions in the development and maintenance of mammalian tissues. These glycosylated receptors have a single hydrophobic transmembrane segment and an intracellular portion which harbors a juxtamembrane segment with a protein kinase domain, and a carboxyterminal tail [2]. Signaling activation of these receptors requires an allosteric interaction between the kinase domains of two receptors where phosphorylation is able to potentiate receptor activity and downstream cell signaling [3]. Mutations, loss of regulation, and aberrant signaling of these ErbB receptors are known to cause many human diseases, most notably cancer [4].

Because of their pivotal role in cell proliferation, maintenance, and survival, inhibitors of tyrosine kinases (TKI) have become useful agents to treat different diseases and now are becoming useful agents in the field of anticancer therapy.

The EGFR plays a key role in cell proliferation and survival, and when mutated activates oncogenic pathways that promote cell survival. One important example of how these growth proteins, if left unchecked, can cause cancer is the human EGFR 2 (HER2, also known as HER2/neu, receptor tyrosine kinase ErbB-2, CD340), which is known to cause breast cancer. Breast cancer patients that present high levels of these HER2 receptors are categorized as having HER2-positive breast cancer. This category of breast cancer is known to proliferate and spread more rapidly than others. Drugs which target and inhibit this HER2 signaling, such as the TKI lapatinib, are useful treatments for HER2-positive breast cancer patients [5].

Resistance to Chemotherapy

Chemoresistance is a major obstacle in treating cancer patients. Cellular and molecular mechanisms which contribute to chemoresistance include cellular alterations in membrane lipids, drug compartmentalization (in endocytic vesicles), auxiliary induction of emergency response elements, the modification of cell cycle checkpoint proteins, an increase or alteration in the molecules which the drug targets, metabolism (also known as bioinactivation), inhibited apoptotic responses (Bcl-2), increased DNA damage repair, decreased uptake (via downregulation of receptors), and increased drug efflux [6].

Increased drug efflux is primarily caused by the presence (or overexpression) of ATP-binding cassette (ABC) transporters across the cell membrane which “pump out” the substrate-specific drug. ABC transporters are naturally occurring, energy-dependent transporters which utilize the hydrolysis of ATP to transport respective substrates across the cell membrane. There are many subclasses of these ABC transporters endogenously important in the transport of a variety of substrates. In multidrug resistance (MDR), the ABC transporters are found to be overexpressed, transporting structurally dissimilar anticancer drugs out of the tumor, reducing the chemotherapeutic efficiency [7].

Several classic chemotherapies including doxorubicin (adriamycin), paclitaxel, topotecan, and mitoxantrone are known substrates of ABC transporters. The role of ABC-transport-mediated MDR is a significant issue for the efficiency of these chemotherapy drugs to fight cancer.

To overcome the ABC-efflux-mediated MDR, investigators have found predosing of small molecule inhibitors, such as TKIs, with ABC substrate chemotherapies to have effective antitumor activity with limited toxicities [8, 9]. This chapter will reveal and explore how current EGFR and HER2 inhibitors (as shown in Fig. 1) are used as sensitizing agents for cancer chemotherapy and hopefully inspire further investigation and clinical research.

Fig. 1 Selected EFGR and HER2 tyrosine kinase inhibitors able to sensitize cancer to chemotherapy [9, 10].

EGFR and HER2 Inhibitors as Sensitizing Agents to Chemotherapy

Gefitinib

Gefitinib, also known as Iressa and ZD1839, was the first EGFR inhibitor approved by the US FDA in May 2003 [11]. Gefitinib is a selective inhibitor of EGFR (ErbB1) used in the treatment of patients with advanced nonsmall-cell lung cancer (NSCLC) [11–13]. Mechanistically, gefitinib binds to the ATP-rich site of EGFR's tyrosine kinase and inhibits its phosphorylation, resulting in blockade of cyclin-dependent kinase activity and a G1 phase cell cycle arrest [14–16].

Besides being a drug of choice for NSCLC, gefitinib has shown potent anticancer activity against ovarian, breast, and colon cancers, when combined with other chemotherapeutic agents [17]. As a sensitizing agent, gefitinib has shown to inhibit the efflux function of ABC transporters and have increased the efficacy of their respective substrates. In 2004, Ozvegy-Laczka et al. [18] reported for the first time that gefitinib can inhibit the efflux function of ABCG2 and sensitizes ABCG2 overexpressing cells to SN-38, a substrate of ABCG2. A year later, pioneer work of Yoichi Nakamura et al. [19] showed that gefitinib, at 10 μM, in combination with a topoisomerase I inhibitor (topotecan), reverses ABCG2-mediated drug resistance and enhances the intracellular accumulation of topotecan, SN-38, and mitoxantrone in ABCG2 overexpressing human small-cell lung cancer. In addition, Lopez et al. [20] investigated gefitinib as a tool against a...

Inhaltsverzeichnis

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• About the Editors
• About the Series Editor
• Aims and Scope for Series “Cancer Sensitizing Agents for Chemotherapy”
• Preface
• Chapter 1: EGFR and HER2 Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 2: BCR-ABL Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 3: VEGFR Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 4: ALK Tyrosine Kinase Inhibitors in Drug Sensitization
• Chapter 5: STAT3 Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 6: FLT3 Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 7: Collagen Signaling in Cancer
• Chapter 8: Bruton's Tyrosine Kinase (BTK) Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 9: CDK Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 10: Bcl-2 Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 11: Small Molecule Chemosensitizing Agents: Polo-Like Kinase 1 (Plk1), BRAF and Janus Kinase (JAK) Inhibitors
• Chapter 12: PI3K/AKT Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 13: Proteasome Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Chapter 14: Combining PI3K/Akt/mTOR Inhibition With Chemotherapy
• Chapter 15: MDM2/P53 Inhibitors as Sensitizing Agents for Cancer Chemotherapy
• Index