Cell Death & Differentiation - DR5/WDR12 balances p65 stability promoting sunitinib resistance in renal cell carcinoma

The combination of bezuclastinib and sunitinib generated favorable efficacy outcomes vs historical data in patients with previously treated GIST.

Antiviral drug discovery has traditionally focused on targeting viral proteins, while host-directed strategies remain largely underexplored. Here, present a systematic drug repurposing strategy levera...

Toni Choueiri: The Final Analysis of the JAVELIN Renal 101 trial / Avelumab, axitinib, cancer, ESMO Annals of Oncology, Javelin Renal 101 trial, OncoDaily,

Liu et al. report results from a controlled phase 2 trial demonstrating that stereotactic body radiotherapy added to first-line sunitinib improves response and progression-free survival in treatment-naive oligometastatic renal cell carcinoma. The addition of SBRT results in comparable toxicity to sunitinib alone and favorable quality-of-life trends.

Read the full paper: Stereotactic body radiotherapy plus sunitinib vs. sunitinib alone in treatment-naive oligometastatic renal cell carcinoma: A phase 2 clinical trial

Bezuclastinib plus sunitinib decreased the risk of progression or death by 50% compared with sunitinib monotherapy in GIST.

Chen et al. reveal that clear cell renal cell carcinoma (ccRCC) evades sunitinib-induced cuproptosis via the USP15-MYCBP2-c-Myc axis, which transcriptionally upregulates PDK1/3/4 to promote DLAT phosphorylation and degradation. Disrupting this axis or combining sunitinib with copper ionophores restores cuproptosis and overcomes sunitinib resistance.

This study reveals that PDZK1 loss impairs ULK1-mediated lipophagy, driving lipid droplet accumulation and sunitinib resistance in clear cell renal cell carcinoma. PDZK1 inhibits LEF1 nuclear translocation, enhancing ULK1 transcription. Pharmacological ULK1 activation resensitizes resistant tumors to sunitinib. ULK1 expression strongly correlates with clinical response, establishing it as a therapeutic target and predictive biomarker. ABSTRACT Clear cell renal cell carcinoma (ccRCC) is characterized by aberrant lipid droplet (LD) accumulation, which promotes tumor progression and sunitinib resistance. However, the underlying molecular mechanisms remain incompletely understood. This study shows that reduced PDZK1 expression correlates with LD accumulation and poor prognosis in ccRCC patients. Single-cell RNA sequencing indicates that downregulated PDZK1 expression associates with impaired LD degradation in ccRCC cells. Functional studies demonstrate that PDZK1 inhibits LD accumulation by upregulating ULK1 expression and activating lipophagy, indicating the PDZK1-ULK1 axis as a therapeutic target to enhance sunitinib efficacy. Mechanistically, CUT&Tag analysis reveals that LEF1 directly binds to the ULK1 promoter. PDZK1 interacts with LEF1 via its C-terminus, sequestering LEF1 in the cytoplasm, thereby enhancing ULK1 transcription and autophagy activity. Pharmacological ULK1 activation with LYN-1604 restores sunitinib sensitivity in PDZK1-knockdown cells and synergizes with sunitinib in xenograft models, reducing tumor growth and LD accumulation. Clinical data demonstrate a strong correlation between ULK1 expression levels in tumor tissues and sunitinib response (AUC = 0.9063), suggesting its potential as a predictive biomarker. Collectively, the PDZK1-ULK1 axis regulates LD homeostasis in ccRCC. Targeting this axis via ULK1 activation represents a novel strategy to overcome sunitinib resistance, with ULK1 as a potential biomarker for sunitinib efficacy.