Inhibition of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance to Programmed Cell Death 1 Blockade in Malignant Mesothelioma.
Inhibition of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance to Programmed Cell Death 1 Blockade in Malignant Mesothelioma.
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抑制细胞周期蛋白依赖性激酶 4/6 可克服恶性间皮瘤中对程序性细胞死亡 1 阻断的主要耐药性。
DOI：
10.1016/j.athoracsur.2021.08.054
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发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
Lee HS
中科院分区：
文献类型：
--
作者：
Jang HJ;Truong CY;Lo EM;Holmes HM;Ramos D;Ramineni M;Lee JS;Wang DY;Pietropaolo M;Ripley RT;Burt BM;Lee HS
尽管目前有大量的恶性胸膜间皮瘤（MPM）患者接受PD-1阻断治疗，但对治疗对检查点免疫疗法耐药的合理治疗策略的基础的认识仍未实现。我们的目标是开发一种新的治疗方法，以克服MPM对PD-1阻断的原发性耐药性。我们在用纳武单抗治疗的MPM患者中产生了对PD-1阻断的抗性的转录组特征（四个应答者和四个无应答者）。我们使用TCGA MPM队列（N=73）来确定哪些基因组改变与耐药特征相关。我们在免疫活性小鼠恶性间皮瘤模型中测试了鉴定的分子的调节是否可以克服对PD-1阻断的抗性。通过将我们的抗PD-1抗性特征应用于TCGA队列的免疫基因组学分析显示，CDKN 2A的缺失与对PD-1阻断的原发性抗性高度相关。在对PD-1阻断的抗性可以通过CDK 4/6抑制来克服的假设下，我们测试了CDK 4/6抑制剂是否可以克服来自Cdkn 2a（−/−）AB 1恶性间皮瘤细胞的皮下肿瘤对PD-1阻断的抗性，该细胞对PD-1阻断具有抗性。与抗PD-1或CDK 4/6抑制剂单独给药相比，每日口服CDK 4/6抑制剂（abemaciclib或palbociclib）联合腹腔内抗PD-1治疗显著抑制肿瘤生长。我们确定了一个治疗靶点CDK 4/6，通过全面的免疫基因组学方法克服对PD-1阻断的原发性耐药性。这些数据为在超过40%的表现出CDKN 2A缺失的MPM患者中进行CDK 4/6抑制剂的临床试验提供了依据。
Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (four responders and four non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. Immunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion of CDKN2A was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by CDK4/6 inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a(−/−) AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 or CDK4/6 inhibitor alone. We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.
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影响因子：
28.2
作者：
Hmeljak J;Sanchez-Vega F;Hoadley KA;Shih J;Stewart C;Heiman D;Tarpey P;Danilova L;Drill E;Gibb EA;Bowlby R;Kanchi R;Osmanbeyoglu HU;Sekido Y;Takeshita J;Newton Y;Graim K;Gupta M;Gay CM;Diao L;Gibbs DL;Thorsson V;Iype L;Kantheti H;Severson DT;Ravegnini G;Desmeules P;Jungbluth AA;Travis WD;Dacic S;Chirieac LR;Galateau-Sallé F;Fujimoto J;Husain AN;Silveira HC;Rusch VW;Rintoul RC;Pass H;Kindler H;Zauderer MG;Kwiatkowski DJ;Bueno R;Tsao AS;Creaney J;Lichtenberg T;Leraas K;Bowen J;TCGA Research Network;Felau I;Zenklusen JC;Akbani R;Cherniack AD;Byers LA;Noble MS;Fletcher JA;Robertson AG;Shen R;Aburatani H;Robinson BW;Campbell P;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
8.8
作者：
Jenkins RW;Barbie DA;Flaherty KT
通讯作者：
Flaherty KT
影响因子：
8
作者：
Dean, J. L.;Thangavel, C.;Knudsen, E. S.
通讯作者：
Knudsen, E. S.
影响因子：
20.4
作者：
Quispel-Janssen, Josine;van der Noort, Vincent;Baas, Paul
通讯作者：
Baas, Paul
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP