Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer.

Abstract

Lung cancer represents the leading cause of cancer-related deaths worldwide. Despite great advances in its management with the recent emergence of molecular targeted therapies for non-small-cell lung cancer (NSCLC), relapse of the metastatic disease always occurs within approximately one year. Epidermal growth factor receptor (EGFR) mutant tumours are the prime example of oncogene addiction and clonal evolution in oncology, regarding the emergence of resistance to first- and second-generation EGFR inhibitors. Multiple studies have revealed that the EGFR-T790M gatekeeper mutation is the main cause of tumour escape. Recently, irreversible pyrimidine-based EGFR inhibitors especially designed for this particular setting have shown robust clinical activity. However, similar to first- and second-generation inhibitors, the development of a diversified set of resistance mechanisms in response to these new compounds is an emerging issue. To date, clinical management of this growing number of patients has not been clearly established, even if anecdotal responses to subsequent molecularly guided therapies have been observed. By exhaustively reviewing and classifying all the preclinical and clinical data published on resistance to third-generation EGFR inhibitors in NSCLC, this work reveals the heterogeneity of the mechanisms that a tumour can develop to evade therapeutic pressure. Strategies currently being tested in clinical trials are discussed in light of these findings.

• Authors: C Ricordel, L Friboulet, F Facchinetti, J-C Soria
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 29 Issue suppl_1 Pg. i28-i37 (01 01 2018) ISSN: 1569-8041 [Electronic] England
• PMID: 29462256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Biomarkers, Tumor
• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, immunology, mortality)
• Clinical Trials as Topic
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects, genetics)
• ErbB Receptors (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics, immunology, mortality)
• Mutation (drug effects)
• Progression-Free Survival
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Signal Transduction (drug effects, genetics)
• Tumor Escape (drug effects, genetics)
• Xenograft Model Antitumor Assays