Acquired resistance to AZD9291 as an upfront treatment is dependent on ERK signaling in a preclinical model
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{"title"=>"Acquired resistance to AZD9291 as an upfront treatment is dependent on ERK signaling in a preclinical model", "type"=>"journal", "authors"=>[{"first_name"=>"Bo Mi", "last_name"=>"Ku", "scopus_author_id"=>"56392606200"}, {"first_name"=>"Moon Ki", "last_name"=>"Choi", "scopus_author_id"=>"57201503023"}, {"first_name"=>"Jong Mu", "last_name"=>"Sun", "scopus_author_id"=>"8423851500"}, {"first_name"=>"Se Hoon", "last_name"=>"Lee", "scopus_author_id"=>"57049824400"}, {"first_name"=>"Jin Seok", "last_name"=>"Ahn", "scopus_author_id"=>"56525813200"}, {"first_name"=>"Keunchil", "last_name"=>"Park", "scopus_author_id"=>"7408064384"}, {"first_name"=>"Myung Ju", "last_name"=>"Ahn", "scopus_author_id"=>"7103352186"}], "year"=>2018, "source"=>"PLoS ONE", "identifiers"=>{"doi"=>"10.1371/journal.pone.0194730", "sgr"=>"85045133999", "scopus"=>"2-s2.0-85045133999", "issn"=>"19326203", "pui"=>"621597415"}, "id"=>"fcbdbd45-58b0-30ab-9d4c-39d0317ba108", "abstract"=>"© 2018 Ku et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. AZD9291 (osimertinib) is approved for standard care in patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) after prior EGFR TKI progression. Furthermore, AZD9291 is now being evaluated as a first-line treatment for NSCLC patients with activation EGFR mutations. Based on previous experiments, resistance to AZD9291 as a first-line treatment may also emerge. Thus, identification and understanding of resistance mechanisms to AZD9291 as a first-line treatment can help direct development of future therapies. AZD9291-resistant cells (PC9/AZDR) were established using EGFR inhibitor-naïve PC9 cells. Resistance mechanisms were analyzed using next-generation sequencing (NGS) and a proteome profiler array. Resistance to AZD9291 developed through aberrant activation of ERK signaling by an EGFR-independent mechanism. The combination of a MEK inhibitor with AZD9291 restored the sensitivity of PC9/AZDR cells in vitro and in vivo. PC9/AZDR cells also showed increased MET expression and an HRAS G13R mutation. In addition, maspin expression was higher after AZD9291 treatment in PC9/AZDR cells. Sustained ERK activation confers resistance to AZD9291 as a first-line therapy. Thus, co-targeting EGFR and MEK may be an effective strategy to overcome resistance to AZD9291.", "link"=>"http://www.mendeley.com/research/acquired-resistance-azd9291-upfront-treatment-dependent-erk-signaling-preclinical-model", "reader_count"=>2, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Medicine and Dentistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

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