pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.
pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.
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DOI：
10.1038/s41416-018-0286-4
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发表时间：
2018-11
影响因子：
8.8
通讯作者：
Pierce AJ
中科院分区：
文献类型：
--
作者：
Jones GN;Rooney C;Griffin N;Roudier M;Young LA;Garcia-Trinidad A;Hughes GD;Whiteaker JR;Wilson Z;Odedra R;Zhao L;Ivey RG;Howat WJ;Harrington EA;Barrett JC;Ramos-Montoya A;Lau A;Paulovich AG;Cadogan EB;Pierce AJ
AZD0156和AZD6738分别是DNA损伤的重要传感器/信号通路--共济失调-毛细血管扩张-激酶(ATM)和共济失调-毛细血管扩张突变和RAD3相关(ATR)的有效和选择性抑制剂。我们利用多重靶向-质谱法从一组45个多肽中选择pRAD50(Ser635)作为AZD0156介导的ATM抑制的药效学生物标志物，然后建立并测试了一种临床适用的免疫组织化学方法检测FFPE组织中的pRAD50(Ser635)。我们发现，在所有癌症适应症中，pRAD50的基线水平中等。PRAD50在100%的胃癌(n = 23)、99%的结直肠癌(n = 102)、95%的三阴性乳腺癌(n = 40)和87.5%的多形性胶质母细胞瘤(n = 16)中表达。我们在TNBC患者来源的异种移植模型中展示了AZD0156靶点抑制；其中AZD0156单一治疗或奥拉帕利治疗后导致pRAD50降低34-72%。在结直肠癌异种移植模型中，ATM抑制剂伊立替康治疗后也观察到类似的pRAD50抑制(68%)。使用AZD6738的ATR抑制在ATM熟练模型中增加了pRAD50，而在ATM缺乏模型中观察到相反的结果，这表明ATR抑制后的pRAD50药效学可能是ATM依赖的，可能有助于确定接受ATR抑制剂治疗的患者的ATM功能。总而言之，这些数据支持将pRAD50作为AZD0156和AZD6738药理学的生物标记物用于临床，以阐明临床药代动力学/药效学关系，从而提供建议的第二阶段剂量/时间表。
AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage. We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue. We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34–72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors. Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.
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影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
3.5
作者：
Gilad, S;Khosravi, R;BarShira, A
通讯作者：
BarShira, A
影响因子：
2
作者：
Gao, Jingfang;Zhang, Hong;Sun, Xiao-Feng
通讯作者：
Sun, Xiao-Feng
影响因子：
3.7
作者：
Bhandaru M;Martinka M;McElwee KJ;Rotte A
通讯作者：
Rotte A
影响因子：
3.5
作者：
Gatei, Magtouf;Kijas, Amanda W.;Lavin, Martin F.
通讯作者：
Lavin, Martin F.