Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2024-08-09
DOI
https://doi.org/10.1038/s44321-024-00102-5
Citations
3
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
0.86

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article

Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

Fan Bai, Vikneswari Rajasegaran, Cedric Chuan Young Ng, Tao Xu et al.
3 citations
EMBO Molecular Medicine
Cancer Genomics and Diagnostics
0.86
article

Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

Fan Bai, Vikneswari Rajasegaran, Cedric Chuan Young Ng, Tao Xu, Jing Han Hong, Jing Ying Tan, Xin Sheng Yao, Bin Tean Teh, Jason Yongsheng Chan, Tomoya Fukawa, Xian Zeng, Peiyong Guan, Choon Kiat Ong, Puay Hoon Tan, Chengqiang Mo, Peili Wang, Swe Swe Myint, Suet Far Wong, R. Xiao, Jianfeng Chen, Mei Li, Wei Liu, Yiqing Du, Joe Poh-Sheng Yeong, Jing Yi Lee, Abner Ming Sun Lim, Chao Zhang, Xiuyu Cai
article en
3 citations

Abstract

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.

EMBO Molecular MedicineVol. 16(9)
Agency for Science, Technology and Research (SG), SingHealth (SG), Sun Yat-sen University (CN), Peking University (CN), Singapore General Hospital (SG), Tianjin Medical University Cancer Institute and Hospital (CN), SingHealth Duke-NUS Academic Medical Centre (SG), Peking University People's Hospital (CN), Duke-NUS Medical School (SG), The First Affiliated Hospital, Sun Yat-sen University (CN), National Cancer Centre Singapore (SG), Sun Yat-sen University Cancer Center (CN), Institute of Medical Biology (SG), Genome Institute of Singapore (SG), Hainan Medical University (CN), Tokushima University (JP)
Duke-NUS Medical School, SingHealth, National Natural Science Foundation of China, Sun Yat-sen University, Medical Research Council, National Medical Research Council, Guangzhou Science and Technology Program key projects, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 26%
Cancer Genomics and Diagnostics
0.86
DOIOpen Access PDFOpenAlex
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