Reactivation of p53 as a radiosensitization strategy for mutant p53 cancers treated with high-LET radiotherapy

Abstract

Abstract Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the high-LET RT based on 224Ra sources and APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using Radium-224 (224Ra) source and APR-246. Effects on cell survival, tumor growth, and apoptosis were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to high-LET RT in vivo. APR-246 treatment enhanced sensitivity to high-LET radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining high-LET RT with p53 restoration via APR-246 triggered apoptosis, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.