Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer.
Ann Oncol
; 29(suppl_1): i28-i37, 2018 01 01.
Article
in En
| MEDLINE
| ID: mdl-29462256
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Non-Small-Cell Lung
/
Drug Resistance, Neoplasm
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Protein Kinase Inhibitors
/
Lung Neoplasms
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Ann Oncol
Journal subject:
NEOPLASIAS
Year:
2018
Type:
Article