Unraveling resistance to CDK4/6 inhibitors in ovarian cancer

Ovarian cancer, a leading cause of death among gynecological malignancies, has a poor prognosis and low 5-year survival rate, necessitating new therapeutic strategies. CDK4/6 inhibitors show promise but their efficacy varies, highlighting the need for biomarkers. This study explores TRIM4's role in ovarian cancer's response to CDK4/6 inhibitors, revealing that TRIM4, an E3 ligase, influences sensitivity by modulating hnRNPDL and CDKN2C levels.

The research established patient-derived ovarian cancer organoid models to assess TQB3616, a CDK4/6 inhibitor, efficacy. RNA sequencing and analyses identified TRIM4 as a key gene correlating with drug response. TRIM4 expression was higher in organoids resistant to TQB3616, and this pattern was confirmed in cell lines and clinical samples. The study also found an inverse relationship between TRIM4 and CDK4/6 expression levels.
Mechanistically, TRIM4 interacts with hnRNPDL, targeting it for ubiquitination and degradation. This interaction reduces hnRNPDL levels, which in turn affects CDKN2C expression. hnRNPDL regulates CDKN2C mRNA splicing, and its degradation leads to increased CDKN2C levels, potentially reducing the effectiveness of CDK4/6 inhibitors. The study used various techniques, including immunoprecipitation, GST pull-down assays, and RNA analyses, to confirm the interaction between TRIM4 and hnRNPDL and its impact on CDKN2C expression.
The researchers further demonstrated that reducing TRIM4 expression enhances ovarian cancer cell sensitivity to TQB3616, both in vitro and in vivo. This was shown through cell cycle analyses, apoptosis assays, and tumor growth studies in mice. The combination of TRIM4 siRNA and CDK4/6 inhibitor treatment significantly reduced tumor growth, suggesting a potential therapeutic approach.
In summary, the study provides insights into TRIM4's role in ovarian cancer's response to CDK4/6 inhibitors, highlighting its potential as a biomarker and therapeutic target. By elucidating the TRIM4-hnRNPDL-CDKN2C regulatory axis, the research offers a foundation for developing more effective treatment strategies for ovarian cancer patients.