Hyper-Dependence on NHEJ Enables Synergy Between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma.
Adrian Mariño-EnriquezJan Philipp NovotnyDoga C GulhanIsabella KloosterAntuan V TranMacy KasboMeijun Z LundbergWen-Bin OuDerrick L TaoDaniel F Pilco-JanetaVictor Y MaoFrank T ZenkeBrittaney A LeeperPrafulla C GokhaleGlenn S CowleyLaurence H BakerKarla V BallmanDavid E RootJoachim AlbersPeter J ParkSuzanne GeorgeJonathan A FletcherPublished in: Clinical cancer research : an official journal of the American Association for Cancer Research (2023)
Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.