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10780432ccr171898-sup-185749_3_supp_4617997_p5hbv6.pptx (187.86 kB)

Supplementary fig 5 from Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent

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posted on 2023-03-31, 19:46 authored by Josep M. Piulats, August Vidal, Francisco J. García-Rodríguez, Clara Muñoz, Marga Nadal, Catia Moutinho, María Martínez-Iniesta, Josefina Mora, Agnés Figueras, Elisabet Guinó, Laura Padullés, Àlvaro Aytés, David G. Molleví, Sara Puertas, Carmen Martínez-Fernández, Wilmar Castillo, Merce Juliachs, Victor Moreno, Purificación Muñoz, Milica Stefanovic, Miguel A. Pujana, Enric Condom, Manel Esteller, Josep R. Germà, Gabriel Capella, Lourdes Farré, Albert Morales, Francesc Viñals, Xavier García-del-Muro, Julián Cerón, Alberto Villanueva

Impact of some RNAi clones on cisplatin toxicity in Caenorhabditis elegans adults

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Spanish Ministry of Economy and Competitiveness

Fundació La Marató TV3

Generalitat de Catalunya

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ARTICLE ABSTRACT

Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755–66. ©2018 AACR.

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