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Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability
Peiyong Guan1, Jianfeng Chen2, Chengqiang Mo3
1Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore.
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.
Insights
Collecting duct carcinoma (CDC) is a rare kidney cancer. This study identified KRAS mutations and aristolochic acid exposure as key factors, revealing cell cycle pathways as therapeutic targets for this aggressive cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Collecting duct carcinoma (CDC) is a rare and aggressive kidney cancer subtype.
- Limited understanding of its molecular drivers and etiology due to rarity and lack of models.
- Unmet clinical needs exist for effective treatments.
Purpose of the Study:
- To comprehensively characterize molecular alterations in CDC.
- To identify therapeutic vulnerabilities in CDC.
- To establish and utilize preclinical models for drug screening.
Main Methods:
- Whole-exome and transcriptome sequencing of patient samples.
- Analysis of mutational signatures and pathway dysregulation.
- Drug screening using newly established CDC preclinical models.
Main Results:
- Identified KRAS hotspot mutations (G12A/D/V) in 23% of patients.
- Detected aristolochic acid (AA) exposure signature (SBS22) in 23% of patients, suggesting geographic etiology.
- Found cell cycle-related pathways to be predominantly dysregulated.
- A CDK9 inhibitor (LDC000067) showed specific inhibition of CDC tumor growth in preclinical models.
Conclusions:
- Elucidated key molecular alterations including KRAS mutations and AA exposure in Asian CDC.
- Identified cell-cycle machinery as a significant therapeutic vulnerability.
- The findings lay the groundwork for future clinical trials targeting CDC.
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