SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity

Boysen, Gunther; Rodrigues, Daniel Nava; Rescigno, Pasquale; Seed, George; Dolling, David; Riisnaes, Ruth; Crespo, Mateus; Zafeiriou, Zafeiris; Sumanasuriya, Semini; Bianchini, Diletta; Hunt, Joanne; Moloney, Deirdre; Pérez-López, Raquel; Tunariu, Nina; Miranda, Susana; Figueiredo, Ines; Ferreira, Ana; Christova, Rossitza; Gil, Veronica; Aziz, Shahid; Bertan, Claudia; Oliveira, Flavia M. de; Atkin, Mark; Clarke, Matthew; Goodall, Jane; Sharp, Adam; MacDonald, Theresa Y.; Rubin, Mark A.; Yuan, Wei; Barbieri, Christopher E.; Carreira, Suzanne; Mateo, Joaquín; Bono, Johann S. de

doi:10.1158/1078-0432.ccr-18-0937

Cited by 119 publications

(98 citation statements)

References 29 publications

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“…Increasing evidence indicates that SPOP mutations often cause elevation of its degradation substrates including AR and transcriptional cofactors such as TRIM24, SRC3, and BET proteins (An et al , ; Geng et al , ; Groner et al , ; Blattner et al , ; Zhang et al , ). Consistent with the finding that SPOP‐mutated specimens acquire highest AR activity among different subtypes of PCa (Cancer Genome Atlas Research Network, ), SPOP‐mutated PCa cells are highly sensitive to treatment of androgen inhibitory agent abiraterone when SPOP mutation is co‐occurred with CHD1 deletion (Boysen et al , ), supporting the notion of oncogene addiction. In contrast, PCa‐associated SPOP hotspot mutations such as F133V and W131R confer resistance to BET inhibitors due to upregulation of BET proteins and aberrant occupancy of BRD4 in the genome (Dai et al , ; Zhang et al , ), implying that specific strategies are needed to effectively treat patients with SPOP‐mutated PCa.…”

Section: Discussionsupporting

confidence: 72%

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

Yan

Wang

et al. 2019

EMBO Mol Med

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CULLIN3‐based E3 ubiquitin ligase substrate‐binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient‐derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non‐hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti‐cancer efficacy of NEO2734 in SPOP‐mutated PCa patients.

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Section: Discussionsupporting

confidence: 72%

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

Yan

Wang

et al. 2019

EMBO Mol Med

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“…In further support of this theory is that, in addition to relatively abundant PTEN loss seen in our cohort, all of the cases that had genomic analysis performed showed at least one genetic alteration that has been associated with invasive, and often aggressive, PCa. These alterations include MYC amplification, genomic losses in CHD1 , TP53 , RB1 , chromosome 8p, and BRCA2 mutation . In addition, the oncogenic PIK3CA mutation identified in one of our cases (case 11) has been demonstrated in a mouse model to be sufficient to cause invasive PCa and cooperates with PTEN loss in the development of castrate resistant disease (CRPC) .…”

Section: Discussionmentioning

confidence: 68%

Intraductal carcinoma of the prostate in the absence of high‐grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Khani

Wobker

Hicks

et al. 2019

The Journal of Pathology

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Intraductal carcinoma of the prostate (IDC‐P) most often appears associated with high‐grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC‐P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low‐grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC‐P (iIDC‐P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC‐P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC‐P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC‐P alterations were similar to those previously described in high‐grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC‐P (BRCA2, CHEK2, CDK12) and other known PCa‐associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC‐P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC‐P and the low‐grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC‐P in four. Despite a CNA profile similar to conventional PCa, iIDC‐P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC‐P is not likely a precursor to the associated low‐grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…15 alterations such as PTEN or CHD1 deletion remain undetectable when ctDNA constitutes a few percent of total cfDNA. Many of the alterations identified by either cfDNA or tissue sequencing alone have clinical relevance, from DDR gene defects and potential sensitivity to PARPi or immunotherapy [25,26], to TP53 and SPOP mutations that infer poor and favourable prognosis, respectively [10,27,28]. Therefore, the optimal approach for correlative studies or biomarker development in the de novo mCSPC setting should incorporate both tissue and plasma analyses, or risk undersampling disease.…”

Section: Discussionmentioning

confidence: 99%

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

et al. 2019

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Word count abstract: 293Word count text: 2592 This is the accepted manuscript of the article, which has been published in European Urology. 2019, 75(4), 667-675. http://dx. AbstractBackground: Several systemic therapeutic options exist for metastatic castratesensitive prostate cancer (mCSPC). Circulating tumour DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer (mCRPC) and can influence decision-making, but remains untested in mCSPC. Objective:To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically-relevant information to a prostate biopsy. Design, Setting, and Participants:We collected plasma cell-free DNA (cfDNA) from 53 newly diagnosed patients with mCSPC and, where possible, during treatment.Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue. Results and Limitations:Median ctDNA fraction was 11% (range 0-84) among untreated patients but lower (1.0%, range 0-51) in patients after short term (median 22 days) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. Concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either are suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should ! 3 utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically-relevant somatic alterations in all patients. Patient summary:In men with advanced prostate cancer, tumour DNA shed into the bloodstream can be measured by a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies.! 4

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SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity

Cited by 119 publications

References 29 publications

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

Intraductal carcinoma of the prostate in the absence of high‐grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

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