Evaluation of deoxynucleosides as a novel resistance mechanism for radiotherapy

摘要

Abstract Lutetium-177 dotatate significantly improves progression free survival, response rate, overall survival and quality of life over standard therapy for patients with gastrointestinal neuroendocrine tumors, however, overall response rates remain low (18%), likely due to endogenous repair of DNA. To repair DNA damaged by lutetium-177 dotatate, cancer cells require deoxyribonucleotide triphosphates, which can be generated by either the de novo or salvage DNA repair pathway. Triapine blocks the de novo pathway, and the combination of lutetium and triapine is being evaluated in the ETCTN trial #10388. However when the de novo pathway is inhibited, the salvage pathway is upregulated and causes resistance to radiation therapy. We propose to measure deoxynucleosides, generated by the salvage pathway, as a biomarker of radiation sensitivity in patients enrolled in ETCTN #10388. In addition, we will evaluate the ability of ATR inhibitors to inhibit the salvage pathway and explore the preclinical activity of the combination of radiation therapy, triapine and ATR inhibition. The proposed aims are highly innovative and would; 1) elucidate a mechanism of resistance for cancer cells to the cytotoxic effects of radiopharmaceuticals and triapine; 2) better resolve the source for single deoxyribonucleosides used in the salvage DNA repair pathway; 3) support the development of a novel combination strategy of triapine and ATR inhibitors to inhibit both the de novo and salvage pathways for DNA repair and enhance the therapeutic activity of lutetium.