DNA Repair in Prostate Cancer: Biology and Clinical Implications

Mateo, Joaquín; Boysen, Gunther; Barbieri, Christopher E.; Bryant, Helen E.; Castro, Elena; Nelson, Peter B.; Olmos, David; Pritchard, Colin C.; Rubin, Mark A.

doi:10.1016/j.eururo.2016.08.037

Cited by 193 publications

(175 citation statements)

References 77 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…In this sample, patients with germline BRCA1/2 mutations had a 23% local failure rate in contrast to only 7% among non-carriers. [4] Other studies have corroborated the association between increased aggressiveness and germline BRCA1/2 lesions; these patients present with higher Gleason scores, have shorter metastasis-free survival and reduced overall survival compared to non-carriers. [5–7] Such patients therefore represent an unmet medical need.…”

Section: Introductionmentioning

confidence: 94%

“…In this context, if HR was also deficient then non-homologous end joining would ensue, producing aberrations within key cellular pathways and trigger cell death. [4, 33] These papers demonstrated large therapeutic indexes for PARP inhibitors in HR-deficient cells, which it was hoped could be leveraged into both extremely effective and well tolerated treatment options in this population at elevated risk for a number of malignancies. [33] Given the high incidence and mortality associated with prostate carcinoma, along with the high rate of HR deficits in metastatic CRPC (approximately 20–25% of cases), there is substantial enthusiasm for developing PARP inhibitors for prostate carcinoma.…”

Section: Need For Further Therapeutic Optionsmentioning

confidence: 99%

“…Poly ADP ribose Polymerases (PARPs) initiate the repair of this damage through the identification of DNA lesions, recruitment of base excision repair pathway machinery, and coordination of the repair process. [4] After identification, repair of SSBs is mediated through a glycosylate, which removes damaged bases, endonuclease activity that eliminates the deoxyribose backbone, and a DNA polymerase that adds the correct nucleotide, utilizing the opposite strand as its template. [3] When SSBs are not effectively repaired, they can progress to double-strand breaks (DSB) which then accumulate in the cell.…”

Section: Scientific Rationalementioning

confidence: 99%

See 2 more Smart Citations

PARP inhibitors for homologous recombination-deficient prostate cancer

Christenson

Antonarakis

2018

Expert Opinion on Emerging Drugs

View full text Add to dashboard Cite

Introduction: Prostate adenocarcinoma represents a leading cause of cancer-related mortality. Increased emphasis on understanding the molecular basis of prostate cancer has identified a substantial burden of homologous recombination (HR) pathway mutations, which are enriched in castrate-resistant disease. This discovery has yielded novel therapeutic opportunities. Areas covered: We will discuss the treatment of castrate-resistant prostate cancer (CRPC), with a focus on the use of poly (ADP-ribose) polymerase (PARP) inhibitors in this space. Evidence for use in HR-deficient patients will be outlined with discussion of the mechanism of action for this drug class, pathways of resistance, and approaches for expanding PARP inhibitor use to non-HR-deficient prostate cancer subgroups. Expert Opinion: PARP inhibition represents an exciting tool for management of HR-inactivated CRPC. With rapid adoption of next-generation sequencing technologies and other molecular techniques, the number of patients in this category is likely to increase. Ongoing and future investigations will be critical for improved understanding of the promise and appropriate treatment sequencing of PARP inhibition and optimal options for HR-proficient and -deficient prostate cancer populations. Questions remain about the clinical significance of monoallelic vs. biallelic HR mutations, the relevance of germline vs. somatic-only mutations, and the importance of mutations in non-canonical HR genes.

show abstract

Section: Introductionmentioning

confidence: 94%

Section: Need For Further Therapeutic Optionsmentioning

confidence: 99%

Section: Scientific Rationalementioning

confidence: 99%

See 1 more Smart Citation

PARP inhibitors for homologous recombination-deficient prostate cancer

Christenson

Antonarakis

2018

Expert Opinion on Emerging Drugs

View full text Add to dashboard Cite

show abstract

“…Notably, DNA damage responses, and predominantly DNA repair, influence the outcome of therapy. Moreover, a substantial association of DNA repairs and drug sensitivity has been demonstrated using cell lines [12]. This indicates a more complex relationship between the efficiency of DNA repair mechanism and tumor therapy.…”

Section: Dna Mismatch Repair Systemmentioning

confidence: 99%

“…PARP inhibition exhibited significant antitumor activity in men with advanced metastatic CRPC, and deleterious germline mutations in BRCA2. Studies have also demonstrated that olaparib would have antitumor activity in sporadic cases of metastatic, CRPC with DNA-repair defects [12].…”

Section: Personalized Treatment Care In Pcamentioning

confidence: 99%

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

Soni¹,

Bansal²

2017

JCPCR

View full text Add to dashboard Cite

Prostate carcinoma (PCa) is among the most frequently diagnosed cancer in men worldwide. Men with metastatic PCa receive primary androgen deprivation therapy (ADT). However, nearly all men will develop resistance to primary ADT, a state known as castration-resistant prostate carcinoma a (CRPC). Several therapeutic drugs with different mechanisms of action have been approved for CRPC including systemic chemotherapeutics (docetaxel and cabazitaxel) and drugs targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. Despite significant survival benefit, resistance to these therapies develops rapidly. Thus, deciphering the mechanisms of resistance and pathways leading to progression is the most critical objectives in PCa research. Some proofof-concept clinical trials have identified that personalized therapies with PARP inhibition, platinum chemotherapy, and immunotherapy may be beneficial to a subset of PCa and CRCP with underlying DNA repair defects. This review aims to address the potential therapeutic implication of Mismatch repair (MMR) pathways in advanced PCa and CRPC.

show abstract

Overexpression of claspin promotes docetaxel resistance and is associated with prostate‐specific antigen recurrence in prostate cancer

et al. 2021

View full text Add to dashboard Cite

Although docetaxel (DTX) confers significant survival benefits in patients with castration‐resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S‐phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin‐positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate‐specific antigen (PSA) relapse‐free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse‐free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX‐resistant DU145 (DU145‐DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145‐DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.

show abstract

DNA Repair in Prostate Cancer: Biology and Clinical Implications

Abstract: Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed.

Cited by 193 publications

References 77 publications

PARP inhibitors for homologous recombination-deficient prostate cancer

PARP inhibitors for homologous recombination-deficient prostate cancer

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

Overexpression of claspin promotes docetaxel resistance and is associated with prostate‐specific antigen recurrence in prostate cancer

Contact Info

Product

Resources

About