Hyper-Dependence on NHEJ Enables Synergy Between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma
Leiomyosarcoma (LMS) is an aggressive sarcoma for which current therapies achieve low response rates. Most LMS have significant chromosomal damage in part from the inactivation of two tumor suppressor genes (TP53 and RB1) and other DNA damage repair defects. In the pre-clinical study, “Hyper-Dependence on NHEJ Enables Synergy Between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma,” the researchers worked to identify therapeutic targets that could take advantage of the DNA damage and cause the tumor cells to die. Using LMS cell lines and mouse models, they demonstrated that inhibition of two proteins (PRKDC (DNA-PKcs) and RPA2) that are involved in a specific type of DNA repair in combination with a low-dose chemotherapy (doxorubicin) had synergistic activity without noticeable toxicity. These findings identify this combination as a potentially clinically actionable in LMS and warrants further investigation.