Current and Future Targeted Therapies for Non-small-cell Lung Cancers With Aberrant EGF Receptors

Shanthi Kanthala; Sandeep Pallerla; Seetharama Jois

Disclosures

Future Oncol. 2015;11(5):865-878. 

In This Article

Abstract and Introduction

Abstract

Expression of the EGF receptors (EGFRs) is abnormally high in many types of cancer, including 25% of lung cancers. Successful treatments target mutations in the EGFR tyrosine kinase domain with EGFR tyrosine kinase inhibitors (TKIs). However, almost all patients develop resistance to this treatment, and acquired resistance to first-generation TKI has prompted the clinical development of a second generation of EGFR TKI. Because of the development of resistance to treatment of TKIs, there is a need to collect genomic information about EGFR levels in non-small-cell lung cancer patients. Herein, we focus on current molecular targets that have therapies available as well as other targets for which therapies will be available in the near future.

Introduction

It is well known that lung cancer is the leading cause of cancer-related deaths in both men and women. Lung cancer causes more deaths annually than the four major cancers – prostate, breast, colon, and pancreatic – combined (American Cancer Society Facts and Figures 2013[1]). Because they are frequently asymptomatic for a long period of time, lung cancers are associated with poor prognosis. Although smoking is considered the leading cause of lung cancer, in 15–20% of lung cancer patients smoking was not observed.[2] Lung cancer is subdivided into two types based on cell type and pathology: small-cell lung cancers and non-small-cell lung cancers (NSCLCs), of which approximately 85% are NSCLCs.[3] NSCLC is subdivided further based on histological phenotypes to squamous-cell carcinoma, large-cell carcinoma and adenocarcinoma (ADC). ADC will occur mostly in distal airways while squamous-cell carcinoma, which occurs in proximal airways, seems to be associated with smoking and chronic inflammation.[4–6] The prognosis of patients with lung cancer is poor, with a survival rate of around one year, making it one of the least understood cancers. Traditional chemotherapeutic agents such as cisplatin, paclitaxel and docetaxel provide standard therapies for lung cancer. However, clinical response is observed in only 30–40% of patients.[7] The overall 5-year survival rate of NSCLC patients is 16%, and this rate decreases rapidly among patients diagnosed at late stages of the disease.[8–10] The quality of life in advanced lung cancer patients is constantly at risk due to treatment toxicity and disease progression. So, increasing the chances of benefit and avoiding futile treatment are very important in the management of the disease. The introduction of targeted therapy in NSCLC gives hope that this may be achieved. Conventional chemotherapy is known to cause adverse toxic effects due to lack of selectivity for tumor cells. The introduction of targeted drugs for the treatment of NSCLC with EGF receptor (EGFR)-directed small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) has had a significant impact. However, as yet, a relatively small overall improvement in clinical outcome has been observed in unselected patients with advanced disease.[11] The key targets of various agents in NSCLC in clinical phases of development include the EGF family of receptors. Various target proteins that have significance in lung cancer are provided in Table 1.[12,13] The aim of this paper is to review the literature and provide a broad understanding of the current and future therapies targeting EGFRs. Additionally, we will cover some issues of resistance in these targeted therapies.

The ErbB family includes four members – EGFR, HER2, HER3 and HER4 – all of which are cell-surface receptor tyrosine kinases (RTKs). Typically, an ErbB receptor is a 170-kDa RTK with an extracellular ligand-binding domain, a transmembrane region and an intracellular tyrosine kinase. The RTKs form homodimers and heterodimers after binding to specific ligands (except HER2, which does not have an endogenous ligand), leading to autophosphorylation of tyrosine residues on the intracellular TK domain. This interaction recruits a diverse set of signaling molecules and cascades, including the PI3K/protein kinase B (Akt)/mTOR, STAT, and RAS/RAF/MAPK proliferation pathway. From 18 to 33% of NSCLC tumors show a positive result (2+/3+) with the HercepTest, a test that evaluates the level of HER2 protein expression on tumor tissue. Testing for mutations in the EGFR gene and rearrangements of the ALK gene in ADC of the lung are now in routine clinical use as predictive genomic biomarkers in the management of advanced lung cancer. Patients with lung ADCs that harbor either of these genomic alterations (15–50%, depending on the population studied) are already benefiting from targeted therapy with oral kinase inhibitors such as erlotinib and crizotinib. Other potential predictive genomic biomarkers in known oncogenes such as BRAF, ROS1, mesenchymal–epithelial transition (MET) and PIK3CA have been identified in a systematic fashion, and efforts are underway to target them with novel drug compounds. Because lung cancer is a heterogeneous group of diseases, it must be targeted using multiple drugs rather than drugs specific to a single target. This review will focus on the rationale for the development of targeted therapies in NSCLC, the recent advances in the therapeutic strategies and agents recently approved by the US FDA for EGFR aberrant lung cancers. In addition, we will discuss various strategies employed in preventing or overcoming the inevitable occurrence of resistance during the treatment and new treatment methods that are underway for NSCLC.

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