Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC.
We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA.
Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner.
DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.
The Prostate. 2023 Oct 09 [Epub ahead of print]
Tung Hoang, Philip Sutera, Triet Nguyen, Jinhee Chang, Shreya Jagtap, Yang Song, Amol C Shetty, Dipanwita D Chowdhury, Aaron Chan, Francesca A Carrieri, Lara Hathout, Ronald Ennis, Salma K Jabbour, Rahul Parikh, Jason Molitoris, Daniel Y Song, Theodore DeWeese, Luigi Marchionni, Lei Ren, Amit Sawant, Nicole Simone, Audrey Lafargue, Kim Van Der Eecken, Fred Bunz, Piet Ost, Phuoc T Tran, Matthew P Deek
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA., Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA., Weill Cornell Medicine, New York, New York, USA., Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Department of Pathology, Ghent University Hospital, Cancer Research Institute (CRIG), Ghent, Belgium., Department of Radiation Oncology, Iridium Network, Antwerp, Belgium.