title: T790M and acquired resistance of EGFR TKI: a literature review of clinical reports.
abstract: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are promising therapies for patients with advanced non-small-cell lung cancer (NSCLC). Patients with somatic activating mutations in the EGFR gene have dramatic response initially, but would eventually develop resistance to these TKIs. Subsequent studies found that a secondary mutation in the EGFR gene (T790M mutation) and amplification of the MET proto-oncogene could be the main resistance mechanisms involved. The current review is focused on T790M, which is thought to cause steric hindrance and impair the binding of gefitinib/erlotinib. The T790M is present as a minor allele before TKI therapy and accounts for about half of the acquired resistant cases. Conflicting results were reported for gefitinib-resistant, T790M-acquired patients who had switched to erlotinib treatment, which was proposed to be efficacious. The switch therapy was presumed to work for EGFR wild type patients and previously gefitinib responding patients. MET amplification accounts for about 20% of TKI acquired-resistant patients by a different molecular pathway from T790M; some of these patients will also concurrently have T790M mutation and might still not respond to irreversible TKI. As for the detection of T790M, polymerase chain reaction (PCR), especially mutant-enriched PCR was found to be more sensitive than direct DNA sequencing. In addition, whole genome amplification might also be useful and can be incorporated with future noninvasive method for detecting T790M. A better understanding of the mechanisms leading to TKI resistance is crucial in the development of effective treatment and the design of future clinical studies.
authors.affiliation: Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ma
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Wei
authors.forename: Yong
authors.initials: Y
authors.lastname: Song