title: EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications.
abstract: Lung cancer is the leading cause of cancer-related death. The identification of epidermal growth factor receptor (EGFR) somatic mutations defined a new, molecularly classified subgroup of non-small-cell lung cancer (NSCLC). Classic EGFR activating mutations, such as inframe deletions in exon 19 or the Leu858Arg (L858R) point mutation in exon 21 are associated with sensitivity to first generation quinazoline reversible EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 insertion mutations, which are typically located after the C-helix of the tyrosine kinase domain of EGFR, may account for up to 4% of all EGFR mutations. Preclinical models have shown that the most prevalent EGFR exon 20 insertion mutated proteins are resistant to clinically achievable doses of reversible (gefitinib, erlotinib) and irreversible (neratinib, afatinib, PF00299804) EGFR TKIs. Growing clinical experience with patients whose tumours harbour EGFR exon 20 insertions corresponds with the preclinical data; very few patients have had responses to EGFR TKIs. Despite the prevalence and biological importance of EEGFR exon 20 insertions, few reports have summarised all preclinical and clinical data on these mutations. Here, we review the literature and provide an update with an emphasis on the structural, molecular, and clinical implications of EGFR exon 20 insertions.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D057285:Precision Medicine; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors