Format

Send to

Choose Destination
Clin Cancer Res. 2019 Jun 10. pii: clincanres.0780.2019. doi: 10.1158/1078-0432.CCR-19-0780. [Epub ahead of print]

The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma.

Author information

1
Yale Cancer Center, Yale School of Medicine.
2
Pathology, Yale University School of Medicine.
3
Department of Medicine, Yale University School of Medicine.
4
Pharmacology, Yale University School of Medicine.
5
Yale Cancer Center, Yale University School of Medicine.
6
Pharmacology, Yale University.
7
Yale University School of Medicine.
8
Department of Medicine (Section of Medical Oncology), Yale University School of Medicine.
9
Biostatistics, Yale University.
10
Dept. Pharmacology and Cancer Biology Institute, Yale University.
11
Department of Medicine (Section of Medical Oncology), Yale School of Medicine.
12
Department of Pathology, Yale University School of Medicine katerina.politi@yale.edu.

Abstract

PURPOSE:

EGFR exon 19 deletion (Ex19Del) mutations account for ~60% of lung cancer-associated EGFR mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKIs), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown.

EXPERIMENTAL DESIGN:

We studied the TKI sensitivity and structural features of common EGFR Exon 19 deletion mutations and the consequences for patient outcomes on TKI treatment.

RESULTS:

We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.

CONCLUSIONS:

These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center