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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.

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Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut.
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut.
Yale Cancer Biology Institute, Yale University, West Haven, Connecticut.
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
Contributed equally



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.


We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.


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.


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

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