Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP1 substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, outcomes for patients with SPOP-mutant (SPOPmut) prostate cancer are heterogeneous and targeted treatments for SPOPmut castrate-resistant prostate cancer (CRPC) are lacking.
Using in silico genomic and transcriptomic tumor data, proteomics analysis and genetically modified cell line models we demonstrate mechanistic links between SPOP mutations, STING signaling alterations and PARP inhibitor vulnerabilities.
We demonstrate that SPOP mutations are associated with upregulation of a 29-gene non-canonical (NC) STING1 (NC-STING) signature in a subset of SPOPmut, treatment-refractory CRPC patients. We show in preclinical CRPC models that SPOP targets and destabilizes STING protein, and prostate cancer ̶ associated SPOP mutations result in upregulated NC-STING-NF-κB signaling and macrophage- and tumor microenvironment (TME)-facilitated reprogramming, leading to tumor cell growth. Importantly, we provide in vitro and in vivo mechanism-based evidence that PARP inhibitor (PARPi) treatment results in a shift from immunosuppressive NC-STING-NF-κB signaling to anti-tumor, canonical cGAS-STING-IFN-β signaling in SPOPmut CRPC and results in enhanced tumor growth inhibition.
We provide evidence that SPOP is critical in regulating immunosuppressive versus anti-tumor activity downstream of DNA damage-induced STING activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, anti-tumor cGAS-STING-IFN-β signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Aug 15 [Epub ahead of print]
Chuandong Geng, Man-Chao Zhang, Ganiraju C Manyam, Jody V Vykoukal, Johannes F Fahrmann, Shan Peng, Cheng Wu, Sanghee Park, Shakuntala Kondraganti, Daoqi Wang, Brian D Robinson, Massimo Loda, Christopher E Barbieri, Timothy A Yap, Paul G Corn, Samir Hanash, Bradley M Broom, Patrick G Pilie, Timothy C Thompson
The University of Texas MD Anderson Cancer Center, Houston, TX, United States., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., UT M. D. Anderson Cancer Center, Houston, TX, United States., Weill Cornell Medicine, New York, NY, United States., New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY, United States., MD Anderson, Houston, Tx, United States.