Targeting MEK1/2 inhibits mitochondrial respiration and redox homeostasis in resistant rectal cancer.

Chemo-resistance is a major challenge in rectal cancer treatment. This study investigates the therapeutic potential of MEK inhibitors, cobimetinib and trametinib, in 5-fluorouracil (5-FU)-resistant rectal cancer cells. High-throughput drug screening identified these inhibitors as top candidates based on their selective drug sensitivity scores (sDSS). Both drugs exhibited dose-dependent cytotoxicity against rectal cancer cells while sparing normal epithelial cells and showed synergistic interactions with 5-FU. MEK inhibition disrupted redox homeostasis, increasing reactive oxygen species (ROS) and oxidative damage markers, including protein carbonyl and malondialdehyde (MDA), while also decreasing mitochondrial respiration, as evidenced by reduced oxygen consumption rates (OCR). Apoptotic induction was significantly reduced in mitochondrial respiration-deficient p⁰ cells, supporting the role of mitochondrial respiration in MEK inhibitor activity. Genetic MEK1/2 knockdown mimicked these effects, confirming MEK1/2 as a key regulator of oxidative stress and mitochondrial respiration. In vivo, cobimetinib and trametinib suppressed tumor growth in a chemo-resistant colorectal cancer xenograft model without significant toxicity, inducing oxidative stress and decreasing mitochondrial respiration. These findings highlight MEK inhibitors as promising candidates for overcoming chemo-resistance in rectal cancer by targeting oxidative stress and mitochondrial respiration.