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. Synopsis: Collecting duct carcinoma (CDC) is an aggressive kidney cancer without effective treatment. Our study not only enhanced our scientific understanding of the oncogenic alterations prevalent in Asian CDC, but has also identified cell-cycle machinery as a potential target for therapeutic intervention. Mutations in KRAS hotspot and TP53 were predominantly identified in Asian CDC patients, shedding light on the genetic landscape of this cancer. Aristolochic acid (AA) mutational signature was identified in CDC tumors, providing valuable insights for cancer prevention strategies. Dysregulation of cell-cycle machinery was observed in both Caucasian and Asian CDC patients, indicating similar disease pathobiology. We have established a CDC patient-derived xenograft (PDX) and cell line models to facilitate drug screening and testing. Through our screening efforts, we have identified and validated a CDK9 inhibitor, LDC000067, which specifically inhibited CDC tumor growth and improved overall survival. Collecting duct carcinoma (CDC) is an aggressive kidney cancer without effective treatment. Our study not only enhanced our scientific understanding of the oncogenic alterations prevalent in Asian CDC, but has also identified cell-cycle machinery as a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]