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Updated: Dec 25, 2025

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
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Rapalog-Mediated Repression of Tribbles Pseudokinase 3 Regulates Pre-mRNA Splicing

Bojana Stefanovska1,2,3, Cecile Edith Vicier1,2,3, Thibault Dayris2,4

  • 1Inserm, UMR981, Villejuif, France.

Cancer Research
|April 5, 2020
PubMed

Insights

Rapalogs fight cancer by disrupting RNA splicing through TRIB3 (tribbles pseudokinase 3). Loss of TRIB3 causes resistance to these therapies, independent of mTOR signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Rapalogs are standard-of-care for metastatic breast, kidney, and neuroendocrine cancers.
  • Tumor resistance to rapalogs develops in most patients, necessitating understanding of resistance mechanisms.

Purpose of the Study:

  • To investigate the role of TRIB3 (tribbles pseudokinase 3) in rapalog resistance.
  • To elucidate the mechanism by which rapalogs induce cytotoxicity and how resistance develops.

Main Methods:

  • Utilized a panel of cancer cell lines and patient blood samples.
  • Investigated the interaction between rapalogs, TRIB3, LRRFIP1, and the spliceosome.
  • Assessed the effect of TRIB3 overexpression on rapalog cytotoxicity.

Main Results:

  • Rapalogs downregulate TRIB3 expression in cancer cell lines and in patients treated with rapalogs.
  • TRIB3 downregulation, mediated by LRRFIP1, disrupts spliceosome interaction and RNA splicing.
  • Overexpression of TRIB3 abrogated the cytotoxic effects of rapalogs.

Conclusions:

  • TRIB3 is a key spliceosome component, and its repression contributes to rapalog resistance.
  • Rapalogs induce cytotoxicity by dysregulating spliceosome function via TRIB3 repression, independent of mTOR signaling.

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