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Antitumor efficacy of XPO1 inhibitor Selinexor in KRAS-mutant lung adenocarcinoma patient-derived xenografts
Translational Oncology ( IF 5 ) Pub Date : 2021-07-17 , DOI: 10.1016/j.tranon.2021.101179
Joshua C Rosen 1 , Jessica Weiss 2 , Nhu-An Pham 3 , Quan Li 3 , Sebastiao N Martins-Filho 3 , Yuhui Wang 3 , Ming-Sound Tsao 4 , Nadeem Moghal 3
Affiliation  

Gain-of-function Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations occur in 25% of lung adenocarcinomas, and these tumors are challenging to treat. Some preclinical work, largely based on cell lines, suggested KRASmut lung cancers are especially dependent on the nuclear export protein exportin-1 (XPO1), while other work supports XPO1 being a broader cancer dependency. To investigate the sensitivity of KRASmut lung cancers to XPO1 inhibition in models that more closely match clinical tumors, we treated 10 independently established lung cancer patient-derived tumor xenografts (PDXs) with the clinical XPO1 inhibitor, Selinexor. Monotherapy with Selinexor reduced tumor growth in all KRASmut PDXs, which included 4 different codon mutations, and was more effective than the clinical MEK1/2 inhibitor, Trametinib. Selinexor was equally effective in KRASG12C and KRASG12D tumors, with TP53 mutations being a biomarker for a weaker drug response. By mining genome-wide dropout datasets, we identified XPO1 as a universal cancer cell dependency and confirmed this functionally in two KRASWT PDX models harboring kinase drivers. However, targeted kinase inhibitors were more effective than Selinexor in these models. Our findings support continued investigation of XPO1 inhibitors in KRASmut lung adenocarcinoma, regardless of the codon alteration.



中文翻译:

XPO1抑制剂Selinexor在KRAS突变肺腺癌患者来源的异种移植物中的抗肿瘤功效

功能获得性 Kirsten 大鼠肉瘤病毒癌基因同源物 ( KRAS ) 突变发生在 25% 的肺腺癌中,这些肿瘤的治疗具有挑战性。一些主要基于细胞系的临床前工作表明,KRAS mut肺癌特别依赖于核输出蛋白 exportin-1 (XPO1),而其他工作则支持 XPO1 是一种更广泛的癌症依赖性。为了在更接近临床肿瘤的模型中研究KRAS mut肺癌对 XPO1 抑制的敏感性,我们用临床 XPO1 抑制剂 Selinexor 治疗了 10 个独立建立的肺癌患者来源的肿瘤异种移植物 (PDX)。单一疗法与Selinexor在所有肿瘤生长减少KRAS MUTPDXs 包括 4 个不同的密码子突变,比临床 MEK1/2 抑制剂曲美替尼更有效。Selinexor 在KRAS G12CKRAS G12D肿瘤中同样有效,TP53突变是药物反应较弱的生物标志物。通过挖掘全基因组辍学数据集,我们将XPO1确定为普遍的癌细胞依赖性,并在两个包含激酶驱动程序的KRAS WT PDX 模型中进行了功能确认。然而,在这些模型中,靶向激酶抑制剂比 Selinexor 更有效。我们的研究结果支持继续研究KRAS mut 中的 XPO1 抑制剂 肺腺癌,无论密码子改变如何。

更新日期:2021-07-18
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