Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment.
Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment.
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DOI：
10.1158/1541-7786.mcr-22-0099
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发表时间：
2022-12-02
影响因子：
5.2
通讯作者：
Wang, Liewei
中科院分区：
文献类型：
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作者：
Sicotte, Hugues;Kalari, Krishna R.;Qin, Sisi;Dehm, Scott M.;Bhargava, Vipul;Gormley, Michael;Tan, Winston;Sinnwell, Jason P.;Hillman, David W.;Li, Ying;Vedell, Peter T.;Carlson, Rachel E.;Bryce, Alan H.;Jimenez, Raphael E.;Weinshilboum, Richard M.;Kohli, Manish;Wang, Liewei
我们在PROMOTE（前列腺癌医学优化基因组增强治疗）研究中确定了转移性去势抵抗性前列腺癌（mCRPC）患者对醋酸阿比特龙/泼尼松（AA/P）的耐药机制。我们分析了来自83例转移性活检患者的全外显子组测序（WES）和RNA-seq数据，这些患者在AA/P治疗前（V1）和12周后（V2）进行了转移性活检。通过治疗时间变化（TTTC）确定耐药性。V2时，58例患者中分别有18例和11例出现短期（中位3.6个月;范围1.4-4.5）或长期（中位29个月;范围23.5-41.7）缓解。治疗前和治疗后，无应答者的TGFBR 3表达较低，Wnt通路活化增加，细胞周期增加，AR变体上调，治疗后AR抑制剂CDK 11B进一步缺失。在治疗后无应答者中观察到雄激素加工基因、HSD 17 B11、CYP 19 A1的缺失。参与细胞周期、DNA修复、Wnt信号传导和Aurora激酶途径的基因在V2时应答者和非应答者之间差异表达。通过体细胞拷贝数（SCN）丢失、体细胞突变和转录组学检测非应答者中Wnt信号传导的激活和应答者中MYC或其靶基因的失活。AURKA通路中基因的上调与无应答者中MYC调节基因的激活一致。AKT 1轴中的几个基因在无应答者中突变率增加。我们还发现了应答者中通过PD 1过表达产生耐药的证据。含义：最后，我们确定了逆转AA/P抗性的候选药物：拓扑异构酶抑制剂和通过MYC/AURKA/AURKB/TOP 2A和/或PI 3 K/AKT 1/MTOR途径靶向细胞周期的药物。
We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the PROMOTE (Prostate Cancer Medically Optimized Genome-Enhanced Therapy) study. We analyzed whole-exome sequencing (WES) and RNA-seq data from 83 patients with metastatic biopsies pre (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC). At V2, 18 and 11 out of 58 patients had either short (median 3.6 months; range 1.4–4.5) or long- (median 29 months; range 23.5–41.7) term responses, respectively. Non-responders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre and post-treatment, with further deletion of AR inhibitor CDK11B post-treatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in non-responders post-treatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in non-responder and deactivation of MYC or its target genes in responders was detected via Somatic Copy Number (SCN) loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in non-responders. Several genes in the AKT1 axis had increased mutation rate in non-responders. We also found evidence of resistance via PD1 overexpression in responders. Implications: Finally, we identified candidates drugs to reverse AA/P resistance : topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K/AKT1/MTOR pathways.