Targeting replication stress as an effective treatment for TP53/RB1-deficient prostate cancers

From the Nelson lab, Human Biology Division

According to statistics from the American Cancer Society, 1 male in 9 will be diagnosed will prostate cancer (PC) during their lifetime. Although most diagnosed men do not die from it, PC is still the second leading cause of cancer death in American males. The principal treatment for PC is androgen deprivation therapy (ADT), which blocks the androgen receptor (AR) signaling pathway. This therapy is initially effective, but resistance can arise after years of responsiveness, leading to poor prognoses and shorter survival times for patients with relapsed PC. This type of cancer is known as castration-resistant prostate cancer (CRPC), and when it spreads beyond the prostate is considered metastatic CRPC (mCRPC). The duration of treatment response varies, and it is likely due to the nature of molecular alterations driving PC progression.

The individual loss of tumor suppressors TP53 and RB1 is observed in 40-50% and 12% of mPCs, respectively, while combined inactivation of both occurs in 4%. Loss of TP53 and/or RB1 is a frequent event it a variety of tumor types. However, it is unclear if the general functions of TP53 and RB1 are responsible for PC progression and treatment resistance or if their loss results in additional alterations in unique aspects of PC biology. Researchers in the Nelson lab (Human Biology Division) evaluated the individual and combinatorial effects of TP53 and RB1 on PC-specific phenotypes and identified a potential target for ADT-resistant tumors with dual TP53 and RB1 loss. The group published the results of the study in the journal Cell Reports.

Schematic for tumor genotype-phenotype in prostate carcinoma.
Prostate carcinoma with loss of tumor suppressors TP53 and RB1 exhibit increased proliferation and stem-like features but reduced AR activity. TP53-/-; RB1-/- tumors develop resistance to androgen receptor signaling inhibitors, but are sensitive to drugs that target replication stress. Image provided by Dr. Peter Nelson.

To establish the phenotypic characteristics of TP53 and RB1 deficient mPCs, Nyquist and colleagues sequenced the protein-coding gene regions from samples of 410 metastatic mCPRC tumors. The samples were classified according to their TP53 and RB1 genomic status. Combined biallelic loss TP53 and RB1 occurred in 5% of tumors, and it was strongly associated with a decrease in AR activity and an increase of stem cell or neuroendocrine (NE) characteristics (46% of all TP53-/-; RB1-/- tumors), which is known to contribute to tumor recurrence and resistance to treatment. Yet, a significant portion of all tumors (35%) retained AR activity and did not exhibit NE program activity. These observations were confirmed by gene expression analyses in double knockout LNCaP cell lines using CRISPR-Cas9 (LNCaP Tp53-/-; RB1-/-); in these cells, the AR program remained active and did not express genes associated with NE programming. Taken together, these results demonstrate that the acquisition of phenotypic plasticity (NE-like features) and loss of AR activity is not an obligate pathway following TP53 and RB1 loss.

Treatment with enzalutemide, anti-androgen drug commonly used for the treatment of CRPC, in LNCaP Tp53-/-; RB1-/- cell lines led to growth suppression, albeit to a lesser extent than WT LNCaP cell lines. These results were then validated in vivo by engrafting mice with LNCaP Tp53-/-; RB1-/- cells. In this model, TP53 and RB1 loss led to shorter time to castration resistance status. Other treatments, known to suppress prostate cancer growth, such as supraphysiological androgen concentrations (SPAs) and ADT, failed to restrict the growth of LNCaP Tp53-/-; RB1-/- cells in vitro compared to WT cells. These results prompted the researchers to identify therapeutics that could repress the growth of TP53 and RB1-deficient PCs. To this end, they tested a panel of FDA approved and bioactive drugs in WT LNCap and LNCaP Tp53-/-; RB1-/- cells; none of the drugs significantly inhibited growth in the TP53/RB1-deficient cells relative to wild type when used as a monotherapy. However, the combination of a PARP inhibitor and an ATR antagonist repressed the growth of these tumors in vitro and in vivo. This finding might reflect on the enhanced replication stress characteristic of TP53 and RB1 dual loss.

 Dr. Nelson, principal investigator in the study, added: “The next step in this study is to move forward and test the hypothesis that a treatment strategy combining a PARP inhibitor and an ATR inhibitor, that together target a vulnerability conferred by replication stress, is effective in patients with tumors that have combined TP53 and RB1 loss. We are moving forward to see if we can encourage industry to support such a trial. A challenge is that ATR inhibitors are not yet approved – but they do look promising in certain cancers.”

This work was supported by the Prostate Cancer Foundation, a Stand Up to Cancer Prostate Cancer Dream Team research grant, grants from the National Cancer Institute, and by a SPORE grants from the Pacific Northwest Prostate Cancer.

Fred Hutch/UW Cancer Consortium members Bruce Montgomery, Colm Morrison, Eva Corey, and Peter Nelson.

Nyquist MD, Corella A, Coleman I, De Sarkar N, Kaipainen A, Ha G, Gulati R, Ang L, Chatterjee P, Lucas J, Pritchard C, Risbridger G, Isaacs J, Montgomery B, Morrissey C, Corey E, Nelson PS. 2020. Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress. Cell Rep. 2020 May 26;31(8):107669. doi: 10.1016/j.celrep.2020.107669. 



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