EMBO Molecular Medicine (Aug 2024)

Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

  • 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

DOI
https://doi.org/10.1038/s44321-024-00102-5
Journal volume & issue
Vol. 16, no. 9
pp. 2132 – 2145

Abstract

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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.

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