Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer.

Igor F Tsigelny,Lyudmila Bazhenova,Razelle Kurzrock,Jennifer J Wheler,David J Stewart,Jerry P Greenberg,Valentina L Kouznetsova

doi:10.18632/oncotarget.3472

Abstract

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene.

Highlights

Patients suffering from lung cancers that harbor epidermal growth factor receptor (EGFR)-sensitive mutations are responsive to reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib [1, 2]
We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents
Patients suffering from lung cancers that harbor EGFR-sensitive mutations are responsive to reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib [1, 2]

Summary

Introduction

Patients suffering from lung cancers that harbor EGFR-sensitive mutations are responsive to reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib [1, 2]. In about 60% of cases initially sensitive to reversible EGFR inhibitors, the T790M mutation emerges; these are generally resistant to both reversible and some irreversible TKIs (e.g., afatinib) in the clinic [3,4,5,6]. A small, but important, subgroup of patients carry EGFR exon insertion mutations (in-frame insertions and/or duplications of 3 to base pairs clustered between codons 767 and 774 in EGFR exon 20), which are known to be generally resistant to both reversible and new irreversible TKIs in the clinic [3]. Shan and colleagues have postulated that EGFR L834R exon 21 mutations ( called L858R) counteract the intrinsic disorder in the EGFR kinase and, facilitate dimerization, which in turn promotes kinase activation [2]

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Results

Conclusion