Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth.
Dewaele, Michael 1,2; Tabaglio, Tommaso 3,4; Willekens, Karen 1,2; Bezzi, Marco 3,4; Teo, Shun Xie 3; Low, Diana H.P. 3; Koh, Cheryl M. 3; Rambow, Florian 1,2; Fiers, Mark 2; Rogiers, Aljosja 1,2; Radaelli, Enrico 5; Al-Haddawi, Muthafar 6; Tan, Soo Yong 6,7; Hermans, Els 8; Amant, Frederic 8,9; Yan, Hualong 10; Lakshmanan, Manikandan 11; Koumar, Ratnacaram Chandrahas 11; Lim, Soon Thye 12; Derheimer, Frederick A. 13; Campbell, Robert M. 13; Bonday, Zahid 13; Tergaonkar, Vinay 11; Shackleton, Mark 14; Blattner, Christine 10; Marine, Jean-Christophe 1,2; Guccione, Ernesto 3,4
[Article]
Journal of Clinical Investigation.
126(1):68-84, January 4, 2016.
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MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target.
Copyright (C) 2016 The American Society for Clinical Investigation, Inc.