Efficacy And Safety Of Hydroxychloroquine Combined With Methotrexate, Capecitabine And Bevacizumab Vs. Regorafenib In Participants With Refractory Metastatic Colorectal Cancer With Mutations In RAS Genes

One potential therapeutic option for pretreated patients with RAS-positive metastatic colorectal cancer (mCRC) could be hydroxychloroquine. The KRAS mutation drives uncontrolled proliferation and cell survival through pathways such as MAPK/ERK and PI3K/AKT. The pathways in KRAS-mutant tumor cells activate autophagy to recycle cellular components and sustain growth under stress conditions, such as hypoxia or nutrient deprivation. Autophagy serves as a pro-survival mechanism, enabling tumor cells to resist intrinsic stressors and treatment, such as chemotherapy or radiation therapy. Hydroxychloroquine inhibits autophagy by blocking the fusion of autophagosomes with lysosomes. This results in the accumulation of damaged organelles and toxic metabolites within the cell, ultimately triggering apoptosis. Suppressing autophagy may also disrupt tumor cell metabolism by increasing oxidative stress. In experimental models, KRAS-mutant tumors demonstrated enhanced sensitivity to autophagy inhibitors such as hydroxychloroquine. In murine studies, combining hydroxychloroquine with chemotherapy or MAPK pathway inhibitors, such as trametinib, augmented antitumor efficacy. Multiple studies have reported that hydroxychloroquine achieves rapid objective responses when combined with targeted therapy or chemotherapy. However, rapid development of acquired resistance remains a challenge. Methotrexate and capecitabine may be considered as options for overcoming acquired resistance to hydroxychloroquine. KRAS-mutant tumors frequently exhibit defects in DNA repair systems. Methotrexate inhibits thymidylate synthesis, causing accumulation of DNA damage, especially uracil misincorporation, which leads to "thymidylate-induced stress" and cell death. Cells with mutations in the KRAS gene may have increased expression of folate transporters, such as RFC or FPGS, making them more sensetive to antifolates such as methotrexate. This increases intracellular drug accumulation and cytotoxic effects. Preclinical studies have shown that exposure to methotrexate in tumor cells with KRAS mutations significantly decreases mRNA expression of the KRAS gene and total levels of KRAS protein. When combined with fluoropyrimidines like capecitabine, methotrexate may enhance suppression of DNA synthesis, which is a critical vulnerability in KRAS-mutant tumors. Capecitabine increases the sensitivity of KRAS-positive tumors to TRAIL-induced apoptosis, a process that may be amplified by hydroxychloroquine exposure. Bevacizumab can be used to improve the delivery of chemotherapy drugs to tumor cells by increasing drug concentration within the tumor through lowering vascular permeability.