Powered by SURFSeq Q！Single-cell transcriptome sequencing Reveals a Positive Feedback Loop Behind Everolimus Resistance in ccRCC

The research team led by Xin-gang Cui from the School of Medicine, Shanghai Jiao Tong University published a research paper titled "PTBP1-Mediated Alternative Splicing of DNAJB6 Promotes Everolimus Resistance in Clear Cell Renal Cell Carcinoma via EIF4B/PKIB/AKT/mTOR Positive Feedback Loop" in Advanced Science (IF 15.6).

Background

Everolimus (EVE) is a key therapy for advanced clear cell renal cell carcinoma (ccRCC), targeting AKT/mTOR signaling. But resistance inevitably emerges, and the mechanisms are poorly understood. Aberrant alternative splicing—particularly driven by PTBP1—may be a critical enabler of this resistance.

Highlights

• PTBP1 is a resistance marker – Single-cell transcriptomics reveals PTBP1 is upregulated in EVE-resistant tumors and its expression positively correlates with AKT/mTOR pathway activation.
• Splicing rewires the cell – PTBP1 promotes the expression of the DNAJB6b isoform through alternative splicing, switching the cellular program toward survival.
• A deadly protein partnership – DNAJB6b directly binds EIF4B, forming a complex that enhances oncogenic translation and activates a PKIB-dependent AKT/mTOR signaling cascade.
• The feedback loop that won’t quit – This cascade creates a positive feedback loop, sustaining oncogenic translation and allowing cancer cells to evade therapy.

Conclusion

PTBP1 drives everolimus resistance in ccRCC by upregulating DNAJB6b, which recruits EIF4B to initiate a PKIB/AKT/mTOR positive feedback loop—offering a promising target to overcome therapeutic evasion.

Single-cell transcriptome sequencing in this research was conducted on the GeneMind SURFSeq Q platform. Learn more about the platform here: https://en.genemind.com/product/surfseq-q