Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

Li, Likun; Karanika, Styliani; Yang, Guang; Wang, Jiangxiang; Park, Sanghee; Broom, Bradley M.; Manyam, Ganiraju C.; Wu, Wenhui; Luo, Yunping; Basourakos, Spyridon P.; Song, Jian; Gallick, Gary E.; Karantanos, Theodoros; Korentzelos, Dimitrios; Azad, Abul Kalam; Kim, Jeri; Corn, Paul G.; Aparicio, Ana; Logothetis, Christopher J.; Troncoso, P.; Heffernan, Timothy P.; Toniatti, Carlo; Lee, Hyun-Sung; Lee, Ju Seog; Zuo, Xiangsheng; Chang, Wenjun; Yin, Jianhua; Thompson, Timothy C.

doi:10.1126/scisignal.aam7479

Cited by 207 publications

(218 citation statements)

References 37 publications

Supporting

Mentioning

199

Contrasting

Order By: Relevance

“…To determine alterations in gene activity that may contribute to ENZ resistance, we conducted a series of cDNA microarray analyses of ENZ‐treated PCa cells. CXCR7 was identified as one of the upregulated genes in ENZ‐treated VCaP and LNCaP cells (microarray data are deposited in the Gene Expression Omnibus [http://www.ncbi.nlm.nih.gov/geo/], accession number GSE69249) . Significantly increased CXCR7 mRNA levels were demonstrated by QRT‐PCR in both VCaP and C4‐2B cells after ENZ treatment (Fig.…”

Section: Resultsmentioning

confidence: 97%

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration‐resistant prostate cancer models

Luo

Azad

Karanika

et al. 2018

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4‐2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub‐G1) in VCaP and C4‐2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p‐EGFR (Y1068), p‐AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133‐4 patient‐derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 μm2) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control‐treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors.

show abstract

Section: Resultsmentioning

confidence: 97%

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration‐resistant prostate cancer models

Luo

Azad

Karanika

et al. 2018

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…[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. [35, 36]…”

Section: Need For Further Therapeutic Optionsmentioning

confidence: 99%

“…[36, 48] This upregulation could hinder the efficacy of PARP inhibition in HR-proficient CRPC and explain in part its poor efficacy in unselected populations. Enzalutamide has been noted to suppress the expression of these DNA repair genes in prostate cell lines, potentially recapitulating the HR-depleted state noted in individuals with BRCA1/2 mutations.…”

Section: Current Research Questionsmentioning

confidence: 99%

“…Enzalutamide has been noted to suppress the expression of these DNA repair genes in prostate cell lines, potentially recapitulating the HR-depleted state noted in individuals with BRCA1/2 mutations. [36] Therefore one strategy that has been postulated is the use of enzalutamide (or abiraterone) in combination with PARP inhibition, which may prove complementary in allowing for the expansion of PARP inhibition to the HR-proficient CRPC population. This approach is currently being testing in an ongoing phase 1 trial by Mathew et al, who are evaluating enzalutamide in combination with niraparib in the treatment of unselected CRPC patients.…”

Section: Current Research Questionsmentioning

confidence: 99%

“…This resistance mechanism may allow cancer cells to better compensate for the increased DSBs seen during PARP inhibition. [36]…”

Section: Mechanisms Of Resistancementioning

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

Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

et al. 2018

View full text Add to dashboard Cite

A number of prostate cancer (PCa)‐specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration‐resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first‐line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion‐positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first‐line endocrine therapy for PCa patients with diagnosed BRCAness.

show abstract

Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

Cited by 207 publications

References 37 publications

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration‐resistant prostate cancer models

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration‐resistant prostate cancer models

PARP inhibitors for homologous recombination-deficient prostate cancer

Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

Contact Info

Product

Resources

About