{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T14:09:33Z","timestamp":1770041373155,"version":"3.49.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Intelligence Medicine Project of Chongqing Medical University","award":["ZHYX2019015"],"award-info":[{"award-number":["ZHYX2019015"]}]},{"name":"Intelligence Medicine Project of Chongqing Medical University","award":["YJSZHYX202013"],"award-info":[{"award-number":["YJSZHYX202013"]}]},{"name":"Medical Data Science Academy"},{"name":"Pioneer Natural Science Foundation of Chongqing","award":["cstc2019jcyj-xfkxX0003"],"award-info":[{"award-number":["cstc2019jcyj-xfkxX0003"]}]},{"name":"Special Performance Incentive and Guidance for Research Institutes of Chongqing","award":["cstc2018jxjl130057"],"award-info":[{"award-number":["cstc2018jxjl130057"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Non-small cell lung cancer (NSCLC) is characterized by relatively rapid response to systemic treatments yet inevitable resistance and predisposed to distant metastasis. We thus aimed at performing sequencing analysis to determine genomic events and underlying mechanisms concerning drug resistance in NSCLC. We performed targeted sequencing of 40 medication-relevant genes on plasma samples from 98 NSCLC patients and analyzed impact of genetic alterations on clinical presentation as well as response to systemic treatments. Profiling of multi-omics data from 1024 NSCLC tissues in public datasets was carried out for comparison and validation of identified molecular events implicated in resistance. A genetic association of CYP2D6 deletion with drug resistance was identified through circulating tumor DNA (ctDNA) profiling and response assessment. FCGR3A amplification was potentially involved in resistance to EGFR inhibitors. We further verified our findings in tissue samples and focused on potential resistance mechanisms, which uncovered that depleted CYP2D6 affected a set of genes involved in EMT, oncogenic signaling as well as inflammatory pathways. Tumor microenvironment analysis revealed that NSCLC with CYP2D6 loss manifested increased levels of immunomodulatory gene expressions, PD-L1 expression, relatively high mutational burden and lymphocyte infiltration. DNA methylation alterations were also found to be correlated with mRNA expressions and copy numbers of CYP2D6. Finally, MEK inhibitors were identified by CMap as the prospective therapeutic drugs for CYP2D6 deletion. These analyses identified novel resistance mechanisms to systemic NSCLC treatments and had significant implications for the development of new treatment strategies.<\/jats:p>","DOI":"10.1093\/bib\/bbab187","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:19:09Z","timestamp":1619137149000},"source":"Crossref","is-referenced-by-count":10,"title":["Identification of genetic variations associated with drug resistance in non-small cell lung cancer patients undergoing systemic treatment"],"prefix":"10.1093","volume":"22","author":[{"given":"Ruihan","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Bioinformatics, The Basic Medical School of Chongqing Medical University, China"}]},{"given":"Chuang","family":"Ge","sequence":"additional","affiliation":[{"name":"Clinical Laboratory of Chongqing University Cancer Hospital, China"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Surgery, The First Affiliated Hospital of Chongqing Medical University, China"}]},{"given":"Jing","family":"Song","sequence":"additional","affiliation":[{"name":"Molecular and Tumor Research Center, Chongqing Medical University, China"}]},{"given":"Shiqi","family":"Miao","sequence":"additional","affiliation":[{"name":"Molecular and Tumor Research Center, Chongqing Medical University, China"}]},{"given":"Yongyao","family":"Tang","sequence":"additional","affiliation":[{"name":"Molecular and Tumor Research Center, Chongqing Medical University, China"}]},{"given":"Jiayi","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, The Basic Medical School of Chongqing Medical University, China"}]},{"given":"Weiqi","family":"Nian","sequence":"additional","affiliation":[{"name":"Phase 1 Clinical Trial Center of Chongqing University Cancer Hospital, China"}]},{"given":"Fangzhou","family":"Song","sequence":"additional","affiliation":[{"name":"Molecular and Tumor Research 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