Abstract 1217: Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Prostatic adenocarcinoma (PCa) is the most frequently diagnosed non-cutaneous malignancy and second leading cause of cancer death in men in the US. Although organ-confined disease is manageable, treatment options for disseminated PCa are limited. First-line therapy for metastatic PCa targets the androgen receptor (AR) via androgen deprivation therapy (ADT); however, tumors often recur, displaying reactivation of AR signaling despite continued therapeutic targeting. There is currently no durable treatment for this advanced disease stage, termed castrate-resistant PCa (CRPC). While most localized PCa express wild-type p53, recent high-profile, genome-wide studies identified increased TP53 gene mutation rates in advanced disease (specifically CRPC). Using these data, we noted that the patient-derived, CRPC-specific p53 mutations observed are relatively unique to prostate cancer. These mutations occur in “hotspot” clusters altered in other tumor types, but represent distinct amino acid changes seemingly unique to prostate cancer. While the underlying consequences of these CRPC-specific p53 mutations are unknown, it was hypothesized that their presence in the DNA-binding domain of p53 protein may represent “gain-of-function” (GOF) alterations that direct the transcription factor to alternative, pro-tumorigenic gene targets. Our preliminary findings strongly support this contention and reveal that these p53 mutations are major drivers of CRPC phenotypes. Specifically, our findings demonstrate that mutant p53: 1. Selectively alter p53 activity, based on analyses of PCa-relevant p53 target genes; 2. Compromise DNA damage response; 3. Alter AR signaling and response to AR-directed therapeutics; and 4. Promote transition to castration-resistance. These data are further supported by recent longitudinal studies of patient progression, wherein the R248Q mutation was found to be a key genetic alteration identifying lethal disease. While future investigation will be directed to better understand the specific contribution of individual DDR mutations, it is clear that deregulation of DNA damage repair and response pathways is likely to underlie increased genomic instability that is observed among advanced prostate cancers. Citation Format: Jeffry L. Dean, Jennifer K. Jones, Jonathan F. Goodwin, Karen E. Knudsen. Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2015-1217