Abstract:
:Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo. SIGNIFICANCE: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Starrett JH,Guernet AA,Cuomo ME,Poels KE,van Alderwerelt van Rosenburgh IK,Nagelberg A,Farnsworth D,Price KS,Khan H,Ashtekar KD,Gaefele M,Ayeni D,Stewart TF,Kuhlmann A,Kaech SM,Unni AM,Homer R,Lockwood WW,Michor F,Gdoi
10.1158/0008-5472.CAN-19-3819subject
Has Abstractpub_date
2020-05-15 00:00:00pages
2017-2030issue
10eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-3819journal_volume
80pub_type
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