Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer

Abstract

The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanisms of resistance towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever-evolving and adaptive nature of NSCLC.

Introduction

Lung cancer is the second most commonly diagnosed cancer, with an estimated 2.2 million new cases, and it remains the leading cause of cancer death, with an estimated 1.8 million deaths in 2020 [1]. The biggest risk factor for lung cancer is tobacco smoking [2]. Lung cancer is also associated with passive smoking, genetic susceptibility and exposure to carcinogens from pollution and the occupational environment [3], [4], [5]. About 85 % of the diagnosed lung cancers constitute non-small cell lung cancer (NSCLC), which has two main subtypes, adenocarcinoma (up to 50 %) and squamous cell carcinoma (30 %) [6]. Molecular understanding of lung cancer has geared the development of targeted chemotherapy which is an important foundation in precision medicine. In targeted chemotherapy, EGFR is observed to be amplified in lung cancer and undergoes mutations in response to drug treatment. It has become a biomarker of drug resistance in lung cancers as its amplification or secondary mutations have been observed post-drug treatment [7]. EGFR, also known as HER1/Erbb1, is a tyrosine kinase receptor of the human epidermal growth factor receptor (HER) family which includes HER2 (Erbb2), HER3 (Erbb3) and HER4 (Erbb4). The single-pass transmembrane receptor of EGFR undergoes dimerisation of its extracellular domain upon binding of ligands such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), amphiregulin (AREG), epigen, β-cellulin, heparin-binding EGF (HB-EGF) and epiregulin [8], [9]. This leads to auto-phosphorylation of the intracellular kinase domain of the receptor, and activates various downstream signalling pathways important in various cellular processes such as phosphatidylinositol 3-kinase (P13K), mitogen-activated protein kinase (MAPK) and janus kinase/signal transducer and activator of transcription proteins (JAK/STAT) (Fig. 1) [10], [11]. However, dysregulation of these downstream signalling pathways is often observed in human cancers due to overexpression of EGFR through ligand-dependent or -independent mechanisms [12]. EGFR mutations have been found to cause excessive constitutive activation of the receptor in a ligand-independent fashion [8], [13]. Mutations are generally within exons 18–21, which includes L858R point mutation in exon 21 and deletion in exon 19. Patients with EGFR mutations in advanced-stage cancer will undergo molecular targeted therapy as the standard first-line treatment. On the other hand, patients without EGFR mutations or with an unknown mutation status are treated with systemic cytotoxic chemotherapy [14]. Gefitinib and erlotinib are the first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) approved by the US Food and Drug Administration (FDA) for the treatment of NSCLC [15]. These inhibitors inhibit cell growth and proliferation by binding to the kinase domain of EGFR to regulate its downstream signalling pathways [16]. Afatinib and dacomitinib are irreversible inhibitors with higher affinity towards the kinase domain of EGFR compared to the first-generation EGFR-TKIs and are superior in terms of progression-free survival (PFS) rate. However, NSCLC patients with activating EGFR mutations will acquire resistance; specifically, the T790M mutation will lead to resistance within 9 to 14 months post-treatment with EGFR-TKIs [17]. The T790M mutation accounts for approximately 9 % of activating EGFR mutations and is correlated with poor prognosis for NSCLC patients [18]. The novel third-generation EGFR-TKI osimertinib effectively tackles the metastatic T790M mutation, but its efficacy is also hindered by acquired resistance. Therefore, an understanding of acquired resistance to EGFR-TKIs is crucial in guiding subsequent treatments. In this review, we focused on the various modes of resistance and provided an update on some new potential chemotherapeutic agents to overcome such resistance.