{"title":"奥西替尼加帕博西尼在携带表皮生长因子受体扩增和CDKN2A/2B同源缺失的非小细胞肺癌患者来源异种移植(PDX)/2D/3D培养模型中的抗肿瘤活性","authors":"","doi":"10.1016/j.neo.2024.101039","DOIUrl":null,"url":null,"abstract":"<div><p>Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by <em>in vivo</em> and <em>in vitro</em> antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had <em>CDKN2A</em> homozygous deletion (homdel), while 33.3 % (3/9) had <em>CDKN2B</em> homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype <em>CDK4</em>, 44.4 % (4/9) in <em>CDK6</em>, and 44.4 % (4/9) in <em>EGFR</em>. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had <em>KRAS</em> mutations, and 66.7 % (6/9) had <em>TP53</em> mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous <em>EGFR</em> amp and <em>CDKN2A/2B</em> homdel. The data showed that NSCLC with <em>EGFR</em> amp and <em>CDKN2A/2B</em> homdel were sensitive to combined drugs. Additional oncogenic <em>KRAS</em> mutation reduced the drug's antitumor effect. <em>EGFR</em> amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype <em>EGFR</em> and <em>CDK6</em> amp and <em>CDKN2A/2B</em> homdel in the absence of oncogenic <em>KRAS</em> mutation.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000812/pdfft?md5=9cc763b7d6a91ab8633b0676a2a293ef&pid=1-s2.0-S1476558624000812-main.pdf","citationCount":"0","resultStr":"{\"title\":\"The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions\",\"authors\":\"\",\"doi\":\"10.1016/j.neo.2024.101039\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by <em>in vivo</em> and <em>in vitro</em> antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had <em>CDKN2A</em> homozygous deletion (homdel), while 33.3 % (3/9) had <em>CDKN2B</em> homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype <em>CDK4</em>, 44.4 % (4/9) in <em>CDK6</em>, and 44.4 % (4/9) in <em>EGFR</em>. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had <em>KRAS</em> mutations, and 66.7 % (6/9) had <em>TP53</em> mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous <em>EGFR</em> amp and <em>CDKN2A/2B</em> homdel. The data showed that NSCLC with <em>EGFR</em> amp and <em>CDKN2A/2B</em> homdel were sensitive to combined drugs. Additional oncogenic <em>KRAS</em> mutation reduced the drug's antitumor effect. <em>EGFR</em> amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype <em>EGFR</em> and <em>CDK6</em> amp and <em>CDKN2A/2B</em> homdel in the absence of oncogenic <em>KRAS</em> mutation.</p></div>\",\"PeriodicalId\":18917,\"journal\":{\"name\":\"Neoplasia\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1476558624000812/pdfft?md5=9cc763b7d6a91ab8633b0676a2a293ef&pid=1-s2.0-S1476558624000812-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neoplasia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1476558624000812\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neoplasia","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1476558624000812","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions
Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation.
期刊介绍:
Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.