Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma.

Autor:	Marino-Enriquez A; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Novotny JP; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Gulhan DC; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts., Klooster I; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Tran AV; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts., Kasbo M; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Lundberg MZ; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Ou WB; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, China., Tao DL; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Pilco-Janeta DF; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology, Autonomous University of Barcelona, Barcelona, Spain., Mao VY; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts., Zenke FT; Research Unit Oncology, The Healthcare Business of Merck KGaA, Darmstadt, Germany., Leeper BA; Experimental Therapeutics Core and the Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Gokhale PC; Experimental Therapeutics Core and the Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Cowley GS; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Baker LH; Michigan Medicine, University of Michigan, Ann Arbor, Michigan., Ballman KV; Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York., Root DE; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Albers J; Research Unit Oncology, The Healthcare Business of Merck KGaA, Darmstadt, Germany., Park PJ; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts., George S; Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Fletcher JA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Dec 15; Vol. 29 (24), pp. 5128-5139.
DOI:	10.1158/1078-0432.CCR-23-0998
Abstrakt:	Purpose: Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity. Experimental Design: We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models. Results: Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity. Conclusions: 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. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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