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

Simple Summary 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. Resistance may occur as a result of EGFR-dependent and independent molecular pathways. The first commonly includes T790M, C797S, L792X and L718X mutations, while the latter pertains to HER2 and MET amplifications, gene rearrangements, disruption in PIK3CA, MAPK signaling and SCLC and epithelial-mesenchymal cells transformation. Liquid biopsies detecting mutant cell-free DNA (cfDNA) have a major potential in the detection of mutant clones before they become clinically apparent. Newer-generation TKIs, 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. In EGFR mutant NSCLC metastatic to the brain, the blood-brain barrier (BBB) decreases the ability of TKIs to reach the central nervous system (CNS), acting as an additional resistance factor, which can presently be addressed with osimertinib. The potential of rechallenging EFGR TKIs after chemotherapy and combining it with anti-PD-1 immunotherapeutics remains ambivalent. Harnessing nanocarriers to improve drug delivery in EGFR TKIs-resistant NSCLC has been promising in preclinical settings, but it is yet to be determined in a clinical context. 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.

Automated summary

Resistance to TKIs of EGFR in advanced NSCLC poses a therapeutic challenge, with liquid biopsies and newer-generation TKIs offering potential solutions.