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 1,2,3 , Jennifer J. Wheler 4 , Jerry P. Greenberg 2 , Valentina L. Kouznetsova 1,2 , David J. Stewart 5 , Lyudmila Bazhenova 1 and Razelle Kurzrock 1 1 Center for Personalized Cancer Therapy, Moores UCSD Cancer Center, La Jolla, CA, USA 2 San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA 3 Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA 4 M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA 5 Department of Medicine, University of Ottawa, Ottawa, Canada Correspondence to: Igor F. Tsigelny, email: // Razelle Kurzrock, email: // Keywords : EGFR, adenocarcinoma, lung cancer, reversible TKI inhibitors, irreversible TKI inhibitors Received : December 04, 2014 Accepted : January 21, 2015 Published : February 28, 2015 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.

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