Englander Institute for Precision Medicine

SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor-Induced Growth Suppression.

TitleSPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor-Induced Growth Suppression.
Publication TypeJournal Article
Year of Publication2023
AuthorsGeng C, Zhang M-C, Manyam GC, Vykoukal JV, Fahrmann JF, Peng S, Wu C, Park S, Kondraganti S, Wang D, Robinson BD, Loda M, Barbieri CE, Yap TA, Corn PG, Hanash S, Broom BM, Pilié PG, Thompson TC
JournalClin Cancer Res
Volume29
Issue21
Pagination4464-4478
Date Published2023 Nov 01
ISSN1557-3265
KeywordsHumans, Male, Mutation, NF-kappa B, Nucleotidyltransferases, Poly(ADP-ribose) Polymerase Inhibitors, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Transcription Factors, Tumor Microenvironment
Abstract

PURPOSE: Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP 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.

EXPERIMENTAL DESIGN: 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.

RESULTS: We demonstrate that SPOP mutations are associated with upregulation of a 29-gene noncanonical (NC) STING (NC-STING) signature in a subset of SPOPmut, treatment-refractory CRPC patients. We show in preclinical CRPC models that SPOP targets and destabilizes STING1 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 antitumor, canonical cGAS-STING-IFNβ signaling in SPOPmut CRPC and results in enhanced tumor growth inhibition.

CONCLUSIONS: We provide evidence that SPOP is critical in regulating immunosuppressive versus antitumor activity downstream of DNA damage-induced STING1 activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, antitumor cGAS-STING-IFNβ signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.

DOI10.1158/1078-0432.CCR-23-1439
Alternate JournalClin Cancer Res
PubMed ID37581614
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
R01 CA255074 / CA / NCI NIH HHS / United States
U01 CA224044 / CA / NCI NIH HHS / United States
R21 CA255581 / CA / NCI NIH HHS / United States

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