Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease.

Keywords: EGFR; TKIs; immunotherapy; non-small cell lung cancer; osimertinib; resistance.

Figure 1

Literature search flow diagram.

Figure 2

Mechanisms of resistance to EGFR-TKIs from a cellular perspective. Schematic representation of EGFR-dependent and independent mechanisms of resistance to TKIs. Stars and lightings illustrate protein mutations in the EGFR dependent and independent sides, respectively, red arrows represent inhibitory effects and purple and blue arrows depict activating effects. Resistance to TKIs decreases their inhibitory effect on intracellular signaling cascades associated with abnormal cell proliferation. EGFR: Epidermal Growth Factor Receptor, TKIs: Tyrosine Kinase Inhibitors, CCGA: Cell Cycle Gene Alterations, CCND amps: Cyclin D1 and Cyclin D2 genes amplifications, CCNE1: Cyclin E1 gene amplification, CDK4/6 amps: Cyclin-Dependent Kinase 4 and 6 genes amplification, CDKN2A: CDK inhibitor 2A, SCLC: Small Cell Lung Cancer, EMT: Epithelial Mesenchymal Transformation.

Figure 3

Mechanism of action of amivantamab in EGFR exon 20 insertions. Amivantamab is a human bispecific antibody, which is effective against EGFR with Exon 20 Insertion mutations. Additionally, amivantamab targets the C-MET membrane receptor, which mediates MET amplification, an emerging non-EGFR dependent mechanism of resistance. It yields a quadruple mechanism of action. First of all, it induces Fc independent downregulation of oncogenic signaling by means of downmodulation (1) and/or internalization of EGFR and C-MET membrane receptors and subsequent degradation that leads to apoptosis (2). Its immune-mediated activity is induced by macrophages-mediated ADCT or ADPC (3) as well as ADCC, which is primarily mediated by natural killers. Mobocertinib and poziotinib are additional novel agents with potential activity against NSCLC with EGFR exon 20 insertions. Mobocertinib is an irreversible TKI that selectively targets in-frame EGFRex20ins mutations and poziotinib is a pan-HER irreversible TKI. ADTC: Antibody-Drug Cellular Trogocytosis, ADPC: Antibody-Drug Cellular Phagocytosis, ADCC: Antibody-Drug Cytotoxicity.

Figure 4

An overview of mutations involved in TKIs resistance. They are divided into EGFR-dependent mechanisms (on the blue pyramid) and EGFR-independent mutations (on the yellow pyramid). They are sorted in ascending order based on their frequency. The most frequent aberration lies at the bottom of each pyramid. SCLC: Small Cell Lung Cancer.