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Your search keyword '"Zecchini, VR"' showing total 2 results
Start Over Author "Zecchini, VR" Journal nature communications
2 results on '"Zecchini, VR"'

1. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer

Author

Asim, M, Tarish, F, Zecchini, HI, Sanjiv, K, Gelali, E, Massie, CE, Baridi, A, Warren, AY, Zhao, W, Ogris, C, McDuffus, L-A, Mascalchi, P, Shaw, G, Dev, H, Wadhwa, K, Wijnhoven, P, Forment, JV, Lyons, SR, Lynch, AG, O'Neill, C, Zecchini, VR, Rennie, PS, Baniahmad, A, Tavaré, S, Mills, IG, Galanty, Y, Crosetto, N, Schultz, N, Neal, D, Helleday, T, University of St Andrews. School of Medicine, University of St Andrews. Statistics, University of St Andrews. Population and Behavioural Science Division, and University of St Andrews. Cellular Medicine Division

Subjects
Male, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Science, ~DC~, NDAS, Collagen Type XI, Article, RC0254, Prostatic Neoplasms, Castration-Resistant, SDG 3 - Good Health and Well-being, Receptors, Androgen, Journal Article, Humans, lcsh:Q, BDC, Homologous Recombination, Synthetic Lethal Mutations, lcsh:Science, R2C, Signal Transduction
Abstract

Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer., Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.

Published
2017
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2. Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.

Author

Sciacovelli M, Dugourd A, Jimenez LV, Yang M, Nikitopoulou E, Costa ASH, Tronci L, Caraffini V, Rodrigues P, Schmidt C, Ryan DG, Young T, Zecchini VR, Rossi SH, Massie C, Lohoff C, Masid M, Hatzimanikatis V, Kuppe C, Von Kriegsheim A, Kramann R, Gnanapragasam V, Warren AY, Stewart GD, Erez A, Vanharanta S, Saez-Rodriguez J, and Frezza C

Subjects
Humans, Amino Acids, Branched-Chain, Nitrogen, Arginine metabolism, Cell Line, Tumor, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics
Abstract

Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies., (© 2022. The Author(s).)

Published
2022
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