Skip to Main content Skip to Navigation
Journal articles

Rapalog-mediated repression of Tribbles pseudokinase 3 regulates pre-mRNA splicing

Abstract : Rapalogs have become standard-of-care in patients with metastatic breast, kidney, and neuroendocrine cancers. Nevertheless, tumor escape occurs after several months in most patients, highlighting the need to understand mechanisms of resistance. Using a panel of cancer cell lines, we show that rapalogs downregulate the putative protein kinase TRIB3 (tribbles pseudokinase 3). Blood samples of a small cohort of patients with cancer treated with rapalogs confirmed downregulation of TRIB3. Downregulation of TRIB3 was mediated by LRRFIP1 independently of mTOR and disrupted its interaction with the spliceosome, where it participated in rapalog-induced deregulation of RNA splicing. Conversely, overexpression of TRIB3 in a panel of cancer cell lines abolished the cytotoxic effects of rapalogs. These findings identify TRIB3 as a key component of the spliceosome, whose repression contributes significantly to the mechanism of resistance to rapalog therapy. SIGNIFICANCE: Independent of mTOR signaling, rapalogs induce cytoxicity by dysregulating spliceosome function via repression of TRIB3, the loss of which may, in the long term, contribute to therapeutic resistance.
Document type :
Journal articles
Complete list of metadatas

https://www.hal.inserm.fr/inserm-02768801
Contributor : Olivia Fromigue <>
Submitted on : Thursday, June 4, 2020 - 10:46:11 AM
Last modification on : Friday, October 9, 2020 - 10:02:34 AM

Identifiers

Collections

Citation

Bojana Stefanovska, Cecile Edith Vicier, Thibault Dayris, Vasily Ogryzko, Véronique Scott, et al.. Rapalog-mediated repression of Tribbles pseudokinase 3 regulates pre-mRNA splicing. Cancer Research, American Association for Cancer Research, 2020, 80 (11), pp.2190-2203. ⟨10.1158/0008-5472.CAN-19-2366⟩. ⟨inserm-02768801⟩

Share

Metrics

Record views

47