Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity
- Sanjana Eyunni
- Rahul Mannan
- Yuping Zhang
- Eleanor Young
- Qiuyang Zhang
- Jie Luo
- Matthew Pang
- Somnath Mahapatra
- Jean Ching-Yi Tien
- James M. George
- Mustapha Jaber
- Hamzah Hakkani
- Sandra E. Carson
- Abigail J. Todd
- Noshad Hosseini
- Mahnoor Gondal
- Ryan J. Rebernick
- Xuhong Cao
- Fengyun Su
- Rui Wang
- Rohit Mehra
- Jing Li
- Marcin Cieslik
- Arul M. Chinnaiyan
- Abhijit Parolia
2025-06-26
FOXA1 is altered in 10 to 40% of prostate cancers, yet its oncogenic mechanisms remain uncharacterized in vivo. We developed knock-in mouse models representing distinct classes of FOXA1 mutations. Histopathological and multiomic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction with p53 inactivation, drive androgen-dependent adenocarcinomas through coactivation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. By contrast, Class 2 mutations induce intraluminal plasticity by reprogramming differentiated luminal cells into a progenitor-like state through activation of KLF5 and AP-1 neo-enhancer circuitries, which enables enhanced survival and proliferation even under castrate androgen levels. Our findings establish FOXA1 as a multifaceted oncogene, with distinct mutational classes divergently evolving to drive prostate tumorigenesis or therapy-resistant progression.