The positive feedback loop between SP1 and MAP2K2 significantly drives resistance to VEGFR inhibitors in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is one of the most common and aggressive malignancies of the urinary system. Despite being the first-line treatment for advanced ccRCC, vascular endothelial growth factor receptor inhibitors (VEGFRis) face significant limitations due to both initial and acquired resistance, which impede complete tumor eradication. Using a CRISPR/Cas9 library screening approach, <i>MAP2K2</i> was identified as a resistance-associated gene for three prevalent VEGFRis (Sunitinib, Axitinib, and Sorafenib). A strong positive correlation was observed between MAP2K2 expression and resistance to these VEGFRis. Drug-resistant cell lines established through dose-escalation consistently exhibited elevated MAP2K2 expression and activation of the MEK/ERK signaling pathway. Notably, combining MEK inhibitors (MEKis) with VEGFRis significantly enhanced the sensitivity of these resistant cells, leading to pronounced cell death. Additionally, a positive feedback regulatory mechanism was discovered between SP1 and MAP2K2, wherein SP1 and MAP2K2 could enhance mutual expression, thereby maintaining MEK/ERK pathway activation. This study reveals that MEKis can effectively re-sensitize VEGFRi-resistant cells, offering a promising therapeutic strategy for overcoming VEGFRi resistance in ccRCC.