Rational design of alternative treatment options for radioresistant rectal cancer using patient-derived organoids.

BACKGROUND: Resistance to radiation therapy is a common challenge in the field of oncology. Cancer cells with an increased ability to effectively repair DNA or cells with higher levels of antioxidants are more resistant to radiation. As cancer cells rely on these traits for survival, they may offer vulnerabilities that could be exploited. METHODS: In the current study, rectal cancer organoids that showed different responses to radiation treatment were identified. RNA sequencing was used to compare radioresistant and radiosensitive organoids. In vitro combination drug screens were performed. The selection of drugs was guided by the RNA sequencing results. RESULTS: Radioresistant organoids exhibited superior transcriptional adaptability and activated more DNA repair pathways when irradiated. Additionally, radioresistant organoids displayed enhanced antioxidant metabolism, including pathways related to the detoxification of reactive oxygen species and the synthesis of glutathione. Combinatorial drug screens identified the combination of RRx-001 (an inducer of oxidative stress) with GCLC inhibitor BSO as a highly effective and synergistic drug combination in killing radioresistant organoids. CRISPR-CAS-mediated knockout of GCLC sensitised organoids to RRx-001. CONCLUSION: Combining RRx-001 with the inhibition of GCLC may be a promising alternative treatment strategy in radioresistant rectal cancer.