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

Oncotarget
Igor F TsigelnyRazelle Kurzrock

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 (...Continue Reading

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Citations

Jan 7, 2016·Oncotarget·Razelle Kurzrock, David J Stewart
Mar 12, 2019·Signal Transduction and Targeted Therapy·Simon Vyse, Paul H Huang
Feb 19, 2016·International Journal of Cancer. Journal International Du Cancer·Mengmeng YangQi-Xiang Li
Nov 11, 2020·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Xingzhou PengYongchang Zhang
Sep 29, 2019·Current Medicinal Chemistry·Weiqi Xia, Chunqi Hu
Sep 17, 2021·Nature·Jacqulyne P RobichauxJohn V Heymach
Sep 26, 2021·Nature Reviews. Clinical Oncology·Alex FriedlaenderAlfredo Addeo

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