{"id":"hum0429","version":1,"url":"https://humandbs.dbcls.jp/research/hum0429/v1","datePublished":"2023-11-13","versions":[{"version":1,"datePublished":"2023-11-13"}],"title":{"ja":"CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer","en":"CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer"},"summary":{"aims":{"ja":"KRAS G12C阻害剤は、KRAS G12C変異を保有する非小細胞肺がん（NSCLC）およびその他の固形悪性腫瘍患者において臨床活性を示すものの、複数の耐性機序によって奏効が制限される。KRAS G12C阻害剤（JDQ443）は、SHP2阻害剤（TNO155）と併用することで抗腫瘍活性が増強されことが示唆されているが、この併用療法は現在臨床評価中である。ある種の耐性を克服または予防する合理的な薬剤併用戦略を立てるために、KRAS G12C変異を保有するNSCLC株由来の異種移植モデル（Xenograftマウス）の腫瘍細胞において、JDQ443±TNO155の投与またはPI3Kα阻害剤（アルペリシブ）および/またはCDK4/6阻害剤（リボシクリブ）との併用投与に対する腫瘍の奏効期間を評価し、KRAS G12C/SHP2併用阻害に対する奏効消失に関連する遺伝的機序を検討した。","en":"Although KRAS G12C inhibitors show clinical activity in patients with KRAS G12C mutated Non-Small Cell Lung Cancer (NSCLC) and other solid tumor malignancies, the response is limited by multiple mechanisms of resistance. The KRAS G12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRAS G12C-mutant NSCLC cell-line and investigated the genetic mechanisms associated with loss of response to combined KRAS G12C/SHP2 inhibition."},"methods":{"ja":"Low-pass whole-genome sequencing（lp-WGS）、RNA-seq","en":"Low-pass whole-genome sequencing (lp-WGS), RNA-seq"},"targets":{"ja":"ヒト肺非小細胞がん細胞株（LU99）を移植し、樹立したXenograftマウスの腫瘍組織に対して薬剤の組み合わせによる処理を施した細胞","en":"LU99 tumor-bearing mice treated with either vehicle or quadruple combination regiment (JDQ443 + TNO155 + alpelisib + ribociclib)"},"url":{"ja":null,"en":null}},"listingSummary":{"methods":{"ja":"配列決定\n発現","en":"Sequencing, Expression profiling"},"targets":{"ja":"ヒト肺癌細胞株LU99を移植したマウスの腫瘍組織：計16検体\n（細胞株）","en":"tumor tissue collected from LU99 tumor-bearing mice: total 16 samples\n(Cell-line)"},"typeOfData":{"ja":"NGS\n（WGS、RNA-seq）","en":"NGS\n(WGS, RNA-seq)"}},"releaseNote":{"ja":"ヒト肺非小細胞がん細胞株（LU99）を移植し、樹立したXenograftマウスの腫瘍組織を対象に、薬剤投与の有無による処理を施した細胞より抽出したDNA/RNAを用いたWGS、RNA-seq解析データをfastqファイルにて提供する。","en":"DNAs/RNAs extracted from tumor tissues collected from LU99 tumor-bearing mice with treatment / vehicle condition were used for the WGS and RNA-seq analyses. Fastq files are provided."},"dataProviders":[{"name":{"ja":"Saskia Brachmann","en":"Saskia Brachmann"},"organization":{"name":{"ja":"Novartis Institutes for BioMedical Research","en":"Novartis Institutes for BioMedical Research"}}}],"researchProjects":[{"name":{"ja":"Oncology","en":"Oncology"},"url":{"ja":null,"en":null}}],"grants":[],"relatedPublications":[{"title":"CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer","doi":"https://doi.org/10.1158/0008-5472.can-23-1127","datasets":["JGAD000773"]}],"datasets":["JGAD000773"],"controlledAccessUsers":[]}