XPO1 R749Q Mutation Drives Endometrial Cancer Progression by Activating HIF-1/2α–AXL–PI3K/MAPK Signaling

However, the molecular mechanisms by which XPO1 mutations influence the initiation and progression of endometrial cancer remain unclear. Here, we we discovered an unexpected role of XPO1 R749Q in regulating AXL expression in EC.This study reveals that the XPO1 R749Q mutation drives malignant transformation in endometrial cancer, including enhanced proliferation, migration, and invasion, by activating the PI3K-Akt and MAPK signaling pathways through the HIF1α/HIF2α-AXL axis.

Importantly, the oncogenic effects mediated by the XPO1 R749Q mutation can be effectively suppressed by the AXL inhibitor cabozantinib and the XPO1 inhibitor KPT-330. These findings elucidate the molecular mechanism by which the XPO1 R749Q mutation contributes to endometrial carcinogenesis and provide a compelling therapeutic rationale for targeting the XPO1 R749Q-mutant subtype of endometrial cancer with cabozantinib and KPT-330