Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Abstract

Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

“…Another retrospective study confirmed the minor efficacy of first-generation EGFR TKIs in patients with G718X and L861Q [ 42 ]. Encouraging results come from the clinical activity of amivantamab, a bispecific antibody directed against EGFR and MET tyrosine kinase receptors, and against tumors with EGFR exon 20ins mutations [ 43 ]. However, we have to wait for the conclusion of ongoing phase III studies to better define its role in this patient setting.…”

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

“…Off-target mechanisms of secondary resistance, occurring on different genes, are also possible [ 126 , 128 , 130 ]. So, in a similar manner to that described for many TKIs (notably those targeting EGFR mutations or ALK rearrangements), secondary resistance associated to KRAS G12C inhibitors can be linked to MET amplification [ 143 , 147 , 152 , 160 , 161 ]. A RET fusion can be a mechanism of secondary resistance since RET kinase domain activation leads to oncogenic signaling of the PI3K-AKT, JNKs, and BRAF–MEK–ERK pathways, thus promoting cell survival and tumor promotion [ 162 ].…”

“…Some of the resistant mechanisms are certainly easier to assess with a tissue biopsy (such as a MET amplification) while other mechanisms may be identified using a liquid biopsy and/or a tissue biopsy (such as new KRAS mutations or BRAF mutations) [ 144 , 145 , 147 ]. Moreover, as different mechanisms of resistance occur at progression in patients treated with different TKIs, early detection of this mechanism can be done with blood samples by establishing monitoring, even before the radiological onset of tumor progression [ 160 , 161 ]. However, other mechanisms of resistance, notably histological transformation, can be assessed only with a tissue biopsy.…”

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

“… A simplified scheme of signal transmission in cell and selected target points: EGFR, MEK, PGDFR, PI3K, RAF, and VEGFR for molecularly targeted drugs (protein kinase inhibitors) [ 14 , 15 , 16 , 17 , 18 ]. …”