Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway

Abstract

The Ras-Raf-MEK-ERK pathway is crucial in tumor development and serves as a target for cancer therapies. A promising approach involves inducing cell death in Ras-expressing cells by inhibiting kinases in this pathway. However, the activation of protective autophagy can counteract the antiproliferative effects of these inhibitors, leading to drug resistance. Our research explored whether cellular senescence induced by the HDAC inhibitor sodium butyrate in E1a+cHa-Ras-transformed rat embryo fibroblasts (ERas) and A549 human lung adenocarcinoma cells with Ki-Ras mutations could enhance the tumor-suppressive effects of MEK/ERK inhibition. In control ERas cells, treatment with the MEK/ERK inhibitor PD0325901 for 24 hours caused mitochondrial damage and resulted in some cells undergoing apoptosis. However, activation of AMPK-dependent autophagy mitigated these pro-apoptotic effects, allowing for mitochondrial recovery and increased cell viability. Interestingly, senescent ERas cells did not activate cytoprotective autophagy when the MEK/ERK pathway was inhibited, likely due to a spatial separation of lysosomes and autophagosomes. As a result, these senescent cells could not form autophagolysosomes to eliminate damaged mitochondria, leading to increased apoptosis. Our findings suggest that inhibiting the MEK/ERK pathway in senescent cells offers a novel strategy for targeting Ras-expressing PD0325901 cells.