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Tumor Suppressor Genes in Prostate Cancer – Currently Prognostic, but Soon to Be Predictive?

Tumor suppressor genes play a critical role in prostate cancer progression, with alterations in PTEN, TP53, and RB1 representing some of the most clinically significant genomic events. These alterations define aggressive biological phenotypes and serve as powerful prognostic biomarkers across disease states. However, despite increasing mechanistic and clinical insight, these alterations do not yet consistently dictate therapeutic decision-making outside of selected clinical trials.

PTEN (phosphatase and tensin homolog) is among the most frequently altered tumor suppressor genes in prostate cancer, with loss occurring in approximately 20% of primary tumors and up to 50% of castration-resistant prostate cancer.1 PTEN loss results in constitutive activation of the PI3K–AKT–mTOR signaling pathway, promoting tumor proliferation and mediating resistance to androgen receptor–directed therapies. In localized cancer, PTEN loss, determined by immunohistochemistry, is associated with worse recurrence free survival.2 Most recently, capivasertib, an AKT inhibitor, demonstrated radiographic progression-free survival benefit in patients with PTEN-deficient, defined by 90% or greater cells lacking expression by immunohistochemistry, metastatic hormone-sensitive prostate cancer.3 Beyond AKT inhibition, PTEN loss has also been associated with impaired homologous recombination repair, providing a biologic rationale for sensitivity to PARP inhibition and DNA-damaging therapies. Preclinical studies demonstrate enhanced response to PARP inhibitors in PTEN-deficient prostate cancer models.4

TP53 mutations represent another critical genomic alteration in prostate cancer, occurring in approximately 25–30% of treatment-naïve metastatic cases and exceeding 40% in castration-resistant disease.5 TP53 alterations accumulate with disease progression and treatment pressure. In metastatic castration-resistant prostate cancer, TP53 alterations are associated with shorter time on treatment with androgen receptor pathway inhibitors.6 Direct therapeutic targeting of mutant p53 remains challenging but continues to evolve, with novel agents that can target specific p53 mutants, restore wild-type p53 conformation, and reverse invasive and metastatic phenotypes in TP53-mutant prostate cancer models.7

Loss of RB1 occurs in approximately 20% of metastatic castration-resistant prostate cancers and is strongly associated with poor clinical outcomes.8 RB1 loss disrupts cell-cycle control through derepression of E2F transcriptional programs, driving unchecked proliferation and therapeutic resistance.9 While uncommon in localized disease, RB1 loss becomes enriched during progression to castration resistance and frequently co-occurs with TP53 alterations.10 Combined TP53 and RB1 loss defines a particularly aggressive biological state, with markedly shortened survival compared with either alteration alone. This genotype is closely associated with lineage plasticity and neuroendocrine differentiation, although a substantial subset of tumors retain adenocarcinoma morphology despite molecular features of androgen receptor independence.11 RB1-deficient tumors also exhibit distinct therapeutic vulnerabilities. Loss of RB1 creates dependency on LSD1-mediated transcriptional regulation, rendering tumors sensitive to LSD1 inhibition in preclinical models.12

Tumor suppressor alterations may also help identify patients most likely to benefit from chemotherapy. Combined loss of TP53, RB1, and/or PTEN defines an aggressive variant prostate cancer phenotype characterized by androgen receptor independence, visceral metastases, rapid clinical progression, and poor responses to androgen receptor–directed therapies. This biology provides a mechanistic rationale for sensitivity to cytotoxic chemotherapy, particularly platinum-based regimens. Prospective and retrospective clinical studies have demonstrated meaningful responses to platinum-containing chemotherapy in patients with aggressive variant clinical and molecular features.13 In a randomized phase II study, the addition of carboplatin to cabazitaxel improved progression-free survival compared with cabazitaxel alone, with the greatest benefit observed in patients harboring combined tumor suppressor loss.14 These data support the concept that tumor suppressor genomics may help guide chemotherapy selection in advanced disease, and prospective biomarker-driven trials are currently ongoing.

Current NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer recognize the aggressive biology associated with compound tumor suppressor loss and include cabazitaxel plus carboplatin as a treatment option for patients with aggressive variant metastatic castration-resistant prostate cancer.15 The ASCO guideline on germline and somatic genomic testing for metastatic prostate cancer emphasizes that alterations in PTEN, TP53, and RB1 provide important prognostic information but cautions against using these biomarkers alone to direct therapy outside of clinical trials.16

In summary, alterations in PTEN, TP53, and RB1 define aggressive prostate cancer phenotypes with profound implications. While these tumor suppressor genes currently function primarily as prognostic biomarkers, accumulating evidence suggests they may increasingly inform treatment selection, particularly with respect to chemotherapy and emerging combination strategies. Ongoing and future clinical trials, integrating molecular stratification, will be essential to determine how these alterations can be prospectively leveraged to optimize treatment selection, evaluate novel targeted and combination approaches, and translate biologic insights into routine clinical practice.

Select actively accruing prostate cancer trials evaluating tumor suppressor gene alterations effect with therapy

  • Phase II neoadjuvant intensified androgen deprivation therapy with capivasertib for high-risk localized prostate cancer with PTEN loss (NCT05593497)
  • Predictive value of coexisting TMPRSS2-ERG gene fusion and PTEN deletion in patients with biochemical recurrence status post salvage or radical radiation therapy (NCT02573636)
  • BORXPTEN – Bortezomib for patients with mCRPC and PTEN deletion (NCT06029998)
  • CVL237 (PI3K inhibitor) for advanced tumors with PTEN deficiency (including prostate cancer) (NCT06183736)
  • Phase 1 trial of GT-220F (PI3K inhibitor) for mCRPC (NCT06866795)
  • GUARDIAN-101 – CLSP-1025 for solid tumors that harbor the p53 R175H mutation (including prostate and bladder cancer) (NCT06778863)
  • PYNNACLE – PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation (including prostate cancer) (NCT04585750)
  • ASPIRE – testing the addition of docetaxel to ADT and apalutamide for metastatic castration-sensitive prostate cancer (with focus on effect of those with PTEN, TP53, or RB1 alteration) (NCT06931340)
  • PEAPOD_FOS – Pembrolizumab, carboplatin, and cabazitaxel in aggressive mCRPC (NCT05563558)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.
  2. Lotan TL, Wei W, Morais CL, et al. PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer. Eur Urol Focus. 2016;2:180-188.
  3. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Annal Oncol. 2026;37:53-68.
  4. Mendes-Pereira AM, Martin SA, Brough R, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1:315–322.
  5. Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–243.
  6. Abida W, Cyrta J, Heller G, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428-11436.
  7. Bykov VJN, Eriksson SE, Bianchi J, et al. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018;18:89–102.
  8. Ku SY, Rosario S, Wang Y, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.
  9. Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev. 2016;30:1492–1502.
  10. Aparicio AM, Shen L, Tapia EL, et al. Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers. Clin Cancer Res. 2016;22:1520–1530.
  11. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.
  12. Sehrawat A, Gao L, Wang Y, et al. LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci USA. 2018;115:E4179–E4188.
  13. Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;119:3621–3630.
  14. Corn PG, Heath EI, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial. Lancet Oncol. 2019;20:1432–1443.
  15. National Comprehensive Cancer Network. Prostate Cancer. NCCN Clinical Practice Guidelines in Oncology.
  16. Yu EY, Rumble RB, Agarwal N, et al. Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline. J Clin Oncol. 43:748–758.