Core Insights - Merck (MRK.US) announced that its dual oral therapy Welireg (belzutifan) combined with lenvatinib met one of its primary endpoints for progression-free survival (PFS) in a Phase III trial for advanced renal cell carcinoma (RCC) patients who had disease progression after prior anti-PD-1/L1 therapy [1] Group 1: Clinical Trial Results - The mid-term analysis showed that the combination of belzutifan and lenvatinib demonstrated statistically significant and clinically meaningful improvement in PFS compared to cabozantinib [2] - The combination therapy also showed statistically significant improvement in the key secondary endpoint of objective response rate (ORR) compared to cabozantinib [2] Group 2: Industry Context - RCC is the most common type of kidney cancer, accounting for approximately 90% of kidney cancer diagnoses [2] - In 2022, there were about 435,000 new cases of kidney cancer globally, with approximately 156,000 deaths attributed to the disease [2] - The incidence of RCC is about twice as high in men compared to women, with around 30% of kidney cancer patients diagnosed at an advanced stage [2]

Core Viewpoint - The study reveals that lactylation of YTHDC1 at K82 enhances its phase separation, stabilizing oncogenic mRNA and promoting the progression of renal cell carcinoma (RCC) in a hypoxic environment [2][6][9]. Group 1: Research Findings - The research systematically mapped the lactylation profile of proteins under hypoxic conditions in RCC, focusing on the functional mechanism of YTHDC1 K82 lactylation [2][6]. - Elevated levels of global lysine lactylation (Kla) were found in human RCC tissues and cells, which promotes malignant development of RCC [6][7]. - YTHDC1 K82 lactylation, mediated by p300 under hypoxic conditions, promotes the malignancy of RCC both in vitro and in vivo [6][7]. Group 2: Mechanism of Action - YTHDC1 K82 lactylation enhances the phase separation of YTHDC1, leading to the expansion of nuclear condensates that protect oncogenic transcripts BCL2 and E2F2 from degradation by the PAXT-EXO complex [6][7][9]. - The study highlights that the increased lysine lactylation regulates the stability of YTHDC1 target genes, thereby facilitating the progression of RCC [9]. Group 3: Study Highlights - Quantitative lactylation proteomics analysis revealed high levels of lactylation modification proteins under hypoxic conditions [7]. - The study identifies a novel regulatory pathway involving YTHDC1 lactylation that opens new therapeutic targets in the intersection of tumor metabolism and RNA regulation [2][6].