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Clin Cancer Res. 2019 Jun 10. 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, New Haven, Connecticut.
2
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
3
Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut.
4
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut.
5
Yale Cancer Biology Institute, Yale University, West Haven, Connecticut.
6
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
7
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. katerina.politi@yale.edu.
#
Contributed equally

Abstract

PURPOSE:

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

EXPERIMENTAL DESIGN:

We studied the TKI sensitivity and structural features of common Ex19Del 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.

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