PO.CL01.06 · 临床研究
TRPM4表达预测前列腺癌对Acetalax的敏感性
TRPM4 expression predicts Acetalax sensitivity in prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：晚期和治疗难治性前列腺癌，包括去势抵抗性疾病，凸显了利用可靶向脆弱性开发新治疗策略的必要性。TRPM4是一种钙激活的单价阳离子通道，可调节细胞体积并促进癌症进展。我们的研究表明，Acetalax在TRPM4阳性三阴性乳腺癌中诱导选择性的类肿胀坏死（oncosis-like）细胞死亡，提示存在TRPM4依赖性的易感性。靶向TRPM4可能通过破坏现有治疗未涉及的离子转运和体积调节机制，从而相比现有疗法具有优势。我们检测了前列腺癌中的TRPM4表达和Acetalax活性。
方法：我们在TRPM4高表达或低表达的前列腺癌细胞系中评估了Acetalax敏感性，包括雄激素依赖性（LNCaP）和去势抵抗性模型（PC3、DU145、22Rv1）。通过Western印迹和免疫荧光评估了TRPM4动态变化、细胞肿胀和肿胀坏死相关表型。通过持续药物暴露培养出耐药克隆。使用组织微阵列（TMA）和TCGA分析了患者样本中的TRPM4表达。通过RNA测序检测了TRPM4缺失后的转录组变化。在TRPM4阳性PDX模型中检测了抗肿瘤活性和耐受性。
结果：TRPM4高表达的前列腺癌细胞在Acetalax处理后表现出快速肿胀、膜起泡和TRPM4降解，而TRPM4低表达细胞和缺乏TRPM4的耐药克隆则不受影响。耐药克隆显示TRPM4耗竭，证实TRPM4是应答所必需的。在患者样本中，腺癌中的TRPM4蛋白高于良性增生，TCGA数据集证实肿瘤中TRPM4转录本相对于正常组织增加，而在不同分期或Gleason分级之间差异极小。转录组分析揭示了与TRPM4缺失相关的基因表达变化，包括离子转运、细胞骨架组织和细胞死亡相关通路的改变，并伴随向增殖程序的转变以及应激和炎症信号的减少，这与体积调节网络被破坏一致。在体内，Acetalax以剂量依赖性方式显著抑制TRPM4阳性PDX肿瘤的生长，且无全身毒性。
结论：TRPM4作为前列腺癌中Acetalax应答的靶点和预测性生物标志物。这些发现凸显了一种TRPM4依赖性的治疗脆弱性，并支持针对TRPM4表达的、治疗难治性前列腺癌（包括CRPC）进行生物标志物指导的Acetalax开发。
查看英文原文 English abstract
Background: Advanced and treatment-refractory prostate cancer, including castration-resistant disease, highlights the need for new therapeutic strategies exploiting targetable vulnerabilities. TRPM4, a calcium-activated monovalent cation channel, regulates cell volume and promotes cancer progression. Our research showed that Acetalax induces selective oncosis-like cell death in TRPM4-positive triple-negative breast cancer, suggesting TRPM4-dependent susceptibility. Targeting TRPM4 may offer advantages over existing therapies by disrupting ion-transport and volume-regulatory mechanisms not addressed by current treatments. We examined TRPM4 expression and Acetalax activity in prostate cancer.
Methods: We assessed Acetalax sensitivity in prostate cancer cell lines with high or low TRPM4, including androgen-dependent (LNCaP) and castration-resistant models (PC3, DU145, 22Rv1). TRPM4 dynamics, cellular swelling, and oncosis-associated phenotypes were evaluated by Western blotting and immunofluorescence. Resistant clones were developed by continuous drug exposure. TRPM4 expression in patient samples was analyzed using tissue microarrays (TMAs) and TCGA. Transcriptomic changes following TRPM4 loss were examined by RNA sequencing. Antitumor activity and tolerability were tested in TRPM4-positive PDX models.
Results: TRPM4-high prostate cancer cells exhibited rapid swelling, membrane blebbing, and TRPM4 degradation after Acetalax, whereas TRPM4-low cells and resistant clones lacking TRPM4 were unaffected. Resistant clones showed TRPM4 depletion, confirming TRPM4 is required for responsiveness. In patient samples, TRPM4 protein was higher in adenocarcinoma than benign hyperplasia, and TCGA datasets confirmed increased TRPM4 transcripts in tumors relative to normal tissue, with minimal differences across stage or Gleason grade. Transcriptomic profiling revealed gene-expression changes associated with TRPM4 loss, including alterations in ion transport, cytoskeletal organization, and cell-death-related pathways, with a shift toward proliferative programs and reduced stress and inflammatory signaling consistent with disrupted volume-regulatory networks. In vivo, Acetalax significantly suppressed growth of TRPM4-positive PDX tumors in a dose-dependent manner without systemic toxicity.
Conclusions: TRPM4 functions as a target and predictive biomarker for Acetalax response in prostate cancer. These findings highlight a TRPM4-dependent therapeutic vulnerability and support biomarker-guided development of Acetalax for TRPM4-expressing, treatment-refractory prostate cancer, including CRPC.
利益披露 Disclosure
Y. Hoshi, None..
W. C. Reinhold, None..
D. Taniyama, None..
Y. Inoue, None..
A. Luna, None..
S. Kumar, None..
Y. Juanjuan, None..
N. Roper, None..
N. Takebe, None..
Y. Pommier, None.