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.

中文翻译：

---

Rapalog介导的三磷酸伪激酶3的抑制调节前mRNA剪接。

Rapalogs已成为转移性乳腺癌，肾癌和神经内分泌癌患者的治疗标准。尽管如此，大多数患者在几个月后仍会发生肿瘤逃逸，这凸显了了解耐药机制的必要性。使用一组癌细胞系，我们显示rapalogs下调假定的蛋白激酶TRIB3（引发假激酶3）。一小部分用雷帕胶治疗的癌症患者的血液样本证实了TRIB3的下调。TRIB3的下调是由LRRFIP1独立于mTOR介导的，并破坏了它与剪接体的相互作用，在那里它参与了rapalog诱导的RNA剪接的放松。相反，TRIB3在一组癌细胞系中的过表达消除了雷帕类药物的细胞毒性作用。这些发现确定TRIB3是剪接体的关键成分，其抑制作用显着促进了对雷帕洛单抗的耐药机制。意义：与mTOR信号传导无关，雷帕洛斯通过抑制TRIB3来使剪接体功能失调，从而诱导细胞毒性，从长远来看，其丧失可能有助于治疗耐药性。