Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

EMBO Molecular Medicine

10.1038/s44321-024-00102-5

http://dx.doi.org/10.1038/s44321-024-00102-5

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

09 August 2024

Guan, P., Chen, J., Mo, C., Fukawa, T., Zhang, C., Cai, X., Li, M., Hong, J. H., Chan, J. Y., Ng, C. C. Y., Lee, J. Y., Wong, S. F., Liu, W., Zeng, X., Wang, P., Xiao, R., Rajasegaran, V., Myint, S. S., Lim, A. M. S., … Tan, J. (2024). Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability. EMBO Molecular Medicine, 16(9), 2132–2145. https://doi.org/10.1038/s44321-024-00102-5

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Key Research and Development Program of China - N/A
Grant Reference no. : 2022YFA1304000

This research / project is supported by the National Natural Science Foundation of P. R. China - N/A
Grant Reference no. : 82320108015, 82073391, and 82170188

This research / project is supported by the Guangzhou Science and Technology Program - N/A
Grant Reference no. : 2022B01J1004

This research / project is supported by the SingHealth - SingHealth Academic Clinical Program (ACP) Grant
Grant Reference no. : 08/FY2018/EX(SL)/45-A86

This research / project is supported by the National Medical Research Council (NMRC) - Singapore Translational Research Investigator (STaR) Award
Grant Reference no. : MOH-000248-00

This research was supported by a Tan Yew Oo Professorship in Pathology

This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Young Individual Research Grant (OF-YIRG)
Grant Reference no. : MOH-001152-00

This research was supported by a Khoo Pre-Doctoral Fellowship (Duke-NUS Medical School)

This research / project is supported by the National Cancer Centre - NCC Research Fund
Grant Reference no. :

https://oar.a-star.edu.sg/communities-collections/articles/20996

1757-4684

Genome Institute of Singapore

https://www.embopress.org/doi/epdf/10.1038/s44321-024-00102-5