Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

中文翻译：

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集合管癌治疗脆弱性的综合分子特征。


集合管癌（CDC）是一种侵袭性罕见的肾癌亚型，临床需求尚未得到满足。人们对其潜在的分子改变和病因知之甚少，主要是因为它的稀有性和缺乏临床前模型。本研究旨在全面表征 CDC 的分子改变并确定其治疗漏洞。通过全外显子组和转录组测序，除了已知的 TP53、NF2 突变外，我们还在 3/13 (23%) 的患者中发现了 KRAS 热点突变 (G12A/D/V)。 3/13 (23%) 的患者携带由马兜铃酸 (AA) 暴露引起的突变特征 (SBS22)，已知马兜铃酸在亚洲更为普遍，突出了地质学上特定的疾病病因。我们进一步发现细胞周期相关途径是最主要的失调途径。我们使用新建立的 CDC 临床前模型进行药物筛选，发现了一种 CDK9 抑制剂 LDC000067，它可以特异性抑制 CDC 肿瘤生长并延长生存期。我们的研究不仅提高了我们对亚洲疾病预防控制中心致癌分子改变的理解，而且还确定了细胞周期机制作为治疗脆弱性，为治疗此类侵袭性癌症患者的临床试验奠定了基础。