URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers.

Abstract

Tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) has only limited clinical benefit and reaches a bottleneck due to its drug resistance. Here, through whole transcriptome sequencing (RNA-Seq) and lipidomic analysis, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, we find that p53 binds to the promoter of stearoyl-CoA desaturase 1 (Scd1) and represses its transcription. Therefore, high expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in xenografted models of wild-type p53 liver cancer cell lines. This combination therapy has potential significant clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma

“…Moreover, its combination therapy with sorafenib reveals a more obvious effect compared with the monotherapy of each drug in the subcutaneous xenograft mouse model, suggesting that SREBP1 antagonist promotes the perturbation of sorafenib in HCC. Ding et al [109] found that aramchol exhibits synergy with donafenib to facilitate the ferroptosis of patient-derived HCC organoids, while it identified high expression of unconventional prefoldin RPB5 interactor (URI) and SCD1 triggering sorafenib resistance in HCC patients, especially in the p53 wild-type subclass. Mildronate, a cardioprotective medication, selectively antagonizes OCTN2, thereby inhibiting the growth and lung metastasis of HCC when compared with the control group.…”

Cytoskeletal gene alterations linked to sorafenib resistance in hepatocellular carcinoma

“…Since 2007, sorafenib, an orally administered multipletarget tyrosine kinase inhibitor (TKI), has been consistently used as a first-line treatment for advanced hepatocellular carcinoma (HCC) [1]. The anti-tumor activity of sorafenib is largely ascribed to suppressing tumor cell proliferation, inhibiting antiangiogenic activity, and promoting apoptosis [2][3][4][5][6][7]. However, only a small number of patients can benefit from sorafenib, and this population usually acquires drug resistance within 6 months [8].…”