Blosser Wayne D, Dempsey Jack A, McNulty Ann M, Rao Xi, Ebert Philip J, Lowery Caitlin D, Iversen Philip W, Webster Yue Wang, Donoho Gregory P, Gong Xueqian, Merzoug Farhana F, Buchanan Sean, Boehnke Karsten, Yu Chunping, You Xin Tian, Beckmann Richard P, Wu Wenjuan, McNeely Samuel C, Lin Aimee Bence, Martinez Ricardo
Eli Lilly and Company, Indianapolis, IN, USA.
Eli Lilly and Company, New York, NY, USA.
Oncotarget. 2020 Jan 21;11(3):216-236. doi: 10.18632/oncotarget.27400.
The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms that protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity.
致癌驱动因素、基因组不稳定性和/或DNA损伤修复缺陷的综合影响增加了癌症中的复制应激。具有高复制应激的细胞依赖于像由CHK1调控的那些检查点的上调来生存。先前对CHK1抑制剂普瑞昔替尼的研究表明其在多种癌症类型中均有活性。因此，我们试图（1）确定普瑞昔替尼敏感性的标志物，以及（2）使用代表多种肿瘤类型的临床前模型来定义内在和获得性耐药的分子机制。我们的研究结果表明，虽然细胞周期蛋白E失调是普瑞昔替尼反应的驱动机制，但与这种异常相关的生物标志物缺乏足够的预测能力，无法使其在临床上用于患者选择。对泛癌细胞系面板和模型的转录组分析揭示了E2F靶基因表达与普瑞昔替尼敏感性之间的关联，并确定了与普瑞昔替尼耐药相关的先天免疫基因。功能性RNAi研究支持复制叉组件作为普瑞昔替尼反应调节剂的因果作用。保护细胞免受致癌基因诱导的复制应激的机制可能会保护肿瘤免受CHK1抑制剂诱导的此类应激，从而导致获得性耐药。此外，对普瑞昔替尼的耐药可能受先天免疫影响。
