Landscape of Cyclin Pathway Genomic Alterations Across 5,356 Prostate Cancers: Implications for Targeted Therapeutics

Abstract

The cyclin pathway may confer resistance to standard treatments but also offer novel therapeutic opportunities in prostate cancer. Herein, we analyzed prostate cancer samples (majority metastatic) using comprehensive genomic profiling performed by next‐generation sequencing (315 genes, >500× coverage) for alterations in activating and sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), androgen receptor (AR) gene, and coalterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). Overall, cyclin sensitizing pathway genomic abnormalities were found in 9.7% of the 5,356 tumors. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Alterations in possible resistance genes, RB1 and CCNE1, were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, whereas AR alterations were seen in 20.9% of tumors (~27.3% in anaplastic). Cyclin sensitizing alterations were also more frequently associated with concomitant AR alterations.

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta‐analysis

“…The main characteristics of the eligible studies are shown in Table 1. Overall, 14 studies with 449 patients were included in the meta‐analysis 3,8–10,16–25 . The median number of patients enrolled in each study was 17 (range: 5–218), and the median age ranged from 65 to 77 years.…”

“…Overall, 14 studies with 449 patients were included in the meta-analysis. 3,[8][9][10][16][17][18][19][20][21][22][23][24][25] The median number of patients enrolled in each study Quality assessments were performed on the included studies (details summarized in Table S1). Seven studies were considered good quality, five studies were of moderate quality, and two studies were of poor quality.…”

Elevated serum CEA is associated with liver metastasis and distinctive circulating tumor DNA alterations in patients with castration‐resistant prostate cancer

“…To the best of our knowledge, this is the first study to illustrate a possible correlation between elevated serum CEA and certain ctDNA alterations in CRPC. Amplifications of AR, MYC, CDK6, RAF1, PIK3CA, BRAF , and MET have been observed in patients with prostate cancer, and amplification of KRAS has been documented to drive malignant potential in prostate cells in vitro 9,18–25 . CNAs in KIT and CCNE1 have not been reported in prostate cancer, but they have been associated with poor prognosis and aggressive behavior in other malignancies 26,27 .…”

“…Amplifications of AR, MYC, CDK6, RAF1, PIK3CA, BRAF, and MET have been observed in patients with prostate cancer, and amplification of KRAS has been documented to drive malignant potential in prostate cells in vitro. 9,[18][19][20][21][22][23][24][25] CNAs in KIT and CCNE1 have not been reported in prostate cancer, but they have been associated…”

Copper(II) Complex Containing 4-Fluorophenoxyacetic Acid Hydrazide and 1,10-Phenanthroline: A Prostate Cancer Cell-Selective and Low-Toxic Copper(II) Compound

“…Regarding Cyclin D1, its aberrant expression or amplification promotes the proliferation of malignant prostate cells, which makes it a prognostic marker and a promising therapeutic target [ 34 ]. In addition, preliminary studies suggest that the cyclin pathway in PCa plays an important role in the evolution of the disease to a castration-resistant stage, interacting with androgens [ 35 , 36 ]. Therefore, we suggest that complex 1 acts on hormone-responsive cells to prevent their progression to a more advanced stage of the disease, including the castration-resistant phenotype.…”