MicroRNAs as a drug resistance mechanism to targeted therapies in EGFR-mutated NSCLC: Current implications and future directions

Abstract

The introduction of EGFR-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and prognosis of non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations. However, these patients display disease progression driven by the onset of acquired mechanisms of drug resistance that limit the efficacy of EGFR-TKI to no longer than one year. Moreover, a small fraction of EGFR-mutated NSCLC patients does not benefit from this targeted treatment due to primary (i.e. intrinsic) mechanisms of resistance that preexist prior to TKI drug treatment. Research efforts are focusing on deciphering the distinct molecular mechanisms underlying drug resistance, which should prompt the development of novel antitumor agents that surmount such chemoresistance modalities.

The capability of microRNAs (miRNAs) to regulate the expression of many oncogenic pathways and their central role in lung cancer progression, provided new directions for research on prognostic biomarkers, as well as innovative tools for predicting patients’ response to systemic therapies. Recent evidence suggests that modulation of key miRNAs may also reverse oncogenic signaling pathways, and potentiate the cytotoxic effect of anti-cancer therapies.

In this review, we focus on the putative emerging role of miRNAs in modulating drug resistance to EGFR-TKI treatment in EGFR-mutated NSCLC. Moreover, we discuss the current implications of miRNAs analyses in the clinical setting, using both tissue and liquid biopsies, as well as the future potential use of miRNA-based therapies in overcoming resistance to targeted agents like TKIs.

Introduction

Lung cancer is the second most common malignancy constituting the leading cause of cancer-related deaths worldwide, accounting for >25% of all cancer deaths (Siegel et al., 2018). Even though lung cancer incidence rates are decreasing in the last years, mainly because of changes in smoking habits, the outcome of lung cancer patients remains dismal (Siegel et al., 2018). Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, whereas small-cell lung cancers, which embody a distinct biological entity, constitute the remaining cases (Howlader et al., 2016). Concerning NSCLC, enormous improvements in diagnostic and therapeutic approaches have been made in the past decades. The deeper understanding of NSCLC biology and identification of specific driver mutations have led to the development of targeted treatments that supplanted standard platinum-based chemotherapy in the subset of so-called ‘oncogene-addicted’ NSCLC patients (Network et al., 2014; Ding et al., 2008). The mutations of the Epidermal Growth Factor Receptor (EGFR) gene represent the most common class of targetable genetic aberrations; they can be found in approximately 10–16% of NSCLC patients from Western countries, and this percentage is even higher (up to 50%) in Asian patients (Rosell et al., 2009; Shi et al., 2014). EGFR mutations usually cluster within EGFR exons 18–21, thus impairing the kinase domain of the receptor, that becomes constitutively active, leading to cell proliferation and survival regardless of the presence of the extracellular ligand (Sordella et al., 2004). In-frame deletions in exon 19 and exon 21, and the L858R point mutation are the most frequent mutations (>90%), which confer increased sensitivity to tyrosine kinase inhibitors (TKIs) (Dearden et al., 2013). To date, three generations of TKIs have been developed and tested in the clinical setting: first-generation (gefitinib, erlotinib, and icotinib), second-generation irreversible inhibitors (afatinib and dacomitinib) and highly selective third-generation inhibitors (osimertinib and rociletinib) (Recondo et al., 2018). The introduction of first- and second-generation TKIs for the management of EGFR-driven NSCLC dramatically changed the natural course of the disease. Frontline treatment of patients with these targeted drugs experiences a gain of 3.4–6.9 months in terms of progression-free survival (PFS) over standard chemotherapy (Recondo et al., 2018). However, despite an initial high overall response rate (56–85%), most tumors acquire molecular mechanisms to escape this pathway blocked, resulting in an inexorable progression (Recondo et al., 2018). Over 50% cases of resistance to first- and second-generation TKIs are caused by the onset of the ‘gatekeeper’ mutation T790 M, which compromises the binding of the abovementioned compounds to EGFR and increases the receptor affinity for ATP (Sequist et al., 2011). Third-generation TKI osimertinib can overcome this drug resistance mechanism, and it has proven to be effective in EGFR-mutated NSCLC irrespective of T790 M status. However, the clinical benefit of this drug is limited by the further emergence of drug resistance (Soria et al., 2017). Besides the aforementioned EGFR T790 M mutation leading to detraction of drug binding due to target alteration, other intensively investigated mechanisms of drug resistance in cancer such as overexpression of efflux transporters, increased drug metabolism, epigenetic modifications, DNA damage response and epithelial-to-mesenchymal transition (EMT) were reported (Housman et al., 2014). Another more recently investigated resistance mechanism, lysosomal sequestration, has been described for hydrophobic weak base drugs such as sunitinib and nintedanib (Zhitomirsky and Assaraf, 2016; Gotink et al., 2011; Zhitomirsky and Assaraf, 2017, 2015; Englinger et al., 2017). Focusing on EGFR-mutated NSCLC, secondary EGFR mutations, activation of bypass signaling pathways and histological transformation to small-cell lung cancer constitute peculiar mechanisms that limit the efficacy of EGFR-TKI (Van Der Steen et al., 2018). Thus, an earlier identification of drug resistance mechanisms as well as the development of new strategies to overcome the limitations of EGFR blockade alone, are urgently needed.