Wnt-pathway Activating Mutations Are Associated with Resistance to First-line Abiraterone and Enzalutamide in Castration-resistant Prostate Cancer

Velho, Pedro Isaacsson; Fu, Wei; Wang, Hao; Mirkheshti, Nooshin; Qazi, Fahad; Lima, F.; Shaukat, Farah; Carducci, Michael A.; Denmeade, Samuel R.; Paller, Channing J.; Markowski, Mark C.; Marshall, Catherine Handy; Eisenberger, Mario A.; Antonarakis, Emmanuel S.

doi:10.1016/j.eururo.2019.05.032

Cited by 66 publications

(43 citation statements)

References 35 publications

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“…Similarly, not all men require escalated treatment beyond ADT for HSPC but biomarkers to guide treatment selection remain limited. The findings of TP53 and/or Wnt pathway activating alterations in 5/8 (63%) of our primary samples highlight a potential biomarker for selecting men that should be considered for escalated therapy, preferably with docetaxel rather than a novel ASI [32,62,127]. Though speculative in the hormone sensitive setting, there is mounting evidence these alterations could be useful in guiding treatment selection in CRPC.…”

Section: Discussionmentioning

confidence: 88%

“…TP53 loss is associated with a worse prognosis and decreased response to abiraterone in CRPC. APC loss, through its activation of Wnt signalling, may promote ASI resistance [32,62]. These two features would make docetaxel a better option than an ASI in the first instance for this patient at metastatic relapse.…”

Section: Case A153: Biopsy Right Iliac Crest Corresponding To Metastamentioning

confidence: 99%

“…PI3K and MAPK are intracellular and extracellular signalling pathways, respectively, that are key to the regulation of the cell cycle and, like certain DDR pathways, are therapeutically targetable (manipulable) with inhibitory drugs [30,31]. The Wnt signalling pathway is a cellular pathway involved in cell growth, embryogenesis and cell cycle progression, the activation of which has been implicated in progression to CRPC and treatment resistance [32]. Previous studies have found that approximately 25% of primary PCas harbour PI3K or MAPK pathway alterations while nearly 50% of metastatic CRPC samples have PI3K alterations [6,7] and 32% MAPK amplifications [30].…”

Section: Shared Genomic Landscapementioning

confidence: 99%

“…Despite meeting criteria for perioperative therapy trials, his genomic profile suggests aggressive local therapy will be sufficient. However, should he relapse however, the alterations in Wnt pathway-associated regions could confer resistance to AR targeting agents [32].…”

Section: Case 19011: Left Prostate Tumour Core Biopsymentioning

confidence: 99%

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The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Crumbaker

Chan

Gong

et al. 2020

Cancers

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Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to individualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients; whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour samples were derived from prostate, lymph nodes, bone and brain. Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in individual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an individual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an individual at any stage of the disease.

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Section: Discussionmentioning

confidence: 88%

Section: Case A153: Biopsy Right Iliac Crest Corresponding To Metastamentioning

confidence: 99%

Section: Shared Genomic Landscapementioning

confidence: 99%

Section: Case 19011: Left Prostate Tumour Core Biopsymentioning

confidence: 99%

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The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Crumbaker

Chan

Gong

et al. 2020

Cancers

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“…(2019) [ 68 ] 168 CTC-based TP53 alteration TP53 alteration is superior to any AR-derived marker in predicting AR-targeting agent responsiveness Isaacsson et al. (2020) [ 70 ] 137 Somatic Wnt-activating mutations Decrease the effectiveness of abiraterone and enzalutamide Chung et al. (2019) [ 69 ] 37 CTC-based AR, AR-V7, PSCA, NKX3.1, Wnt5b, PSA Decrease the effectiveness of abiraterone and enzalutamide Annala et al.…”

Section: Genomic Evaluation For Mcrpcmentioning

confidence: 99%

Clinical implications of genomic evaluations for prostate cancer risk stratification, screening, and treatment: a narrative review

Chung

Morgan

Hong

2020

Prostate International

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New classification systems based on molecular features have been introduced to improve precision medicine for prostate cancer (PCa). This review covers the increasing risk of PCa and the differences in response to targeted therapy that are related to specific gene variations. We believe that genomic evaluations will be useful for guiding PCa risk stratification, screening, and treatment. We searched the PubMed and MEDLINE databases for articles related to genomic testing for PCa that were published in 2020 or earlier. There is increasing evidence that germline mutations in DNA repair genes, such as BRCA1/2 or ATM , are closely related to the development and aggressiveness of PCa. Targeted prostate-specific antigen screening based on the presence of germline alterations in DNA repair genes is recommend to achieve an early diagnosis of PCa. In cases of localized PCa, even if it has a favorable risk classification, patients under active surveillance with these gene alterations are likely to develop aggressive PCa. Thus, active treatment may be preferable to active surveillance for these patients. In cases of metastatic castration–resistant PCa, BRCA1/2 and DNA mismatch repair genes may be useful biomarkers for predicting the response to androgen receptor–targeting agents, poly (ADP-ribose) polymerase inhibitors, platinum chemotherapy, prostate-specific membrane antigen–targeted therapy, immunotherapy, and radium-223. Genomic evaluations may allow for risk stratification of patients with PCa based on their molecular features, which may help guide precision medicine for treating PCa.

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Proteome profiling of enzalutamide‐resistant cell lines and serum analysis identified ALCAM as marker of resistance in castration‐resistant prostate cancer

Csizmarik

Keresztes

Nagy

et al. 2022

Intl Journal of Cancer

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Enzalutamide (ENZA) is a frequently used therapy in metastatic castration‐resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy‐predictive serum markers. We performed comparative proteome analyses on ENZA‐sensitive parental (LAPC4, DuCaP) and ‐resistant prostate cancer cell lines (LAPC4‐ENZA, DuCaP‐ENZA) using liquid chromatography tandem mass spectrometry (LC‐MS/MS). The top four most promising candidate markers were selected using bioinformatic approaches. Serum concentrations of selected markers (ALCAM, AGR2, NDRG1, IDH1) were measured in pretreatment samples of 72 ENZA‐treated mCRPC patients using ELISA. In addition, ALCAM serum levels were measured in 101 Abiraterone (ABI) and 100 Docetaxel (DOC)‐treated mCRPC patients' baseline samples. Results were correlated with clinical and follow‐up data. The functional role of ALCAM in ENZA resistance was assessed in vitro using siRNA. Our proteome analyses revealed 731 significantly differentially abundant proteins between ENZA‐sensitive and ‐resistant cells and our filtering methods identified four biomarker candidates. Serum analyses of these proteins revealed only ALCAM to be associated with poor patient survival. Furthermore, higher baseline ALCAM levels were associated with poor survival in ABI‐ but not in DOC‐treated patients. In LAPC4‐ENZA resistant cells, ALCAM silencing by siRNA knockdown resulted in significantly enhanced ENZA sensitivity. Our analyses revealed that ALCAM serum levels may help to identify ENZA‐ and ABI‐resistant patients and may thereby help to optimize future clinical decision‐making. Our functional analyses suggest the possible involvement of ALCAM in ENZA resistance.

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Wnt-pathway Activating Mutations Are Associated with Resistance to First-line Abiraterone and Enzalutamide in Castration-resistant Prostate Cancer

Cited by 66 publications

References 35 publications

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Clinical implications of genomic evaluations for prostate cancer risk stratification, screening, and treatment: a narrative review

Proteome profiling of enzalutamide‐resistant cell lines and serum analysis identified ALCAM as marker of resistance in castration‐resistant prostate cancer

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