2. Academic Validation
  3. Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

  • J Clin Invest. 2016 Jan;126(1):68-84. doi: 10.1172/JCI82534.
Michael Dewaele,  Tommaso Tabaglio,  Karen Willekens,  Marco Bezzi,  Shun Xie Teo,  Diana H P Low,  Cheryl M Koh,  Florian Rambow,  Mark Fiers,  Aljosja Rogiers,  Enrico Radaelli,  Muthafar Al-Haddawi,  Soo Yong Tan,  Els Hermans,  Frederic Amant,  Hualong Yan,  Manikandan Lakshmanan,  Ratnacaram Chandrahas Koumar,  Soon Thye Lim,  Frederick A Derheimer,  Robert M Campbell,  Zahid Bonday,  Vinay Tergaonkar,  Mark Shackleton,  Christine Blattner,  Jean-Christophe Marine,  Ernesto Guccione
PMID: 26595814 DOI: 10.1172/JCI82534
Abstract

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.

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