title: Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer.
abstract: Triple-negative breast cancers have unfavorable outcomes due to their inherent aggressive behavior and lack of targeted therapies. Breast cancers occurring in BRCA1 mutation carriers are mostly triple-negative and harbor homologous recombination deficiency, sensitizing them to inhibition of a second DNA damage repair pathway by, e.g., PARP inhibitors. Unfortunately, resistance against PARP inhibitors in BRCA1-deficient cancers is common and sensitivity is limited in BRCA1-proficient breast cancers. RK-33, an inhibitor of the RNA helicase DDX3, was previously demonstrated to impede non-homologous end-joining repair of DNA breaks. Consequently, we evaluated DDX3 as a therapeutic target in BRCA pro- and deficient breast cancers and assessed whether DDX3 inhibition could sensitize cells to PARP inhibition. High DDX3 expression was identified by immunohistochemistry in breast cancer samples of 24% of BRCA1 (p = 0.337) and 21% of BRCA2 mutation carriers (p = 0.624), as compared to 30% of sporadic breast cancer samples. The sensitivity to the DDX3 inhibitor RK-33 was similar in BRCA1 pro- and deficient breast cancer cell lines, with IC50 values in the low micromolar range (2.8-6.6 μM). A synergistic interaction was observed for combination treatment with RK-33 and the PARP inhibitor olaparib in BRCA1-proficient breast cancer, with the mean combination index ranging from 0.59 to 0.62. Overall, we conclude that BRCA pro- and deficient breast cancers have a similar dependency upon DDX3. DDX3 inhibition by RK-33 synergizes with PARP inhibitor treatment, especially in breast cancers with a BRCA1-proficient background.
authors.affiliation: Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.|Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Marise R
authors.initials: MR
authors.lastname: Heerma van Voss
authors.affiliation: Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Brilliant
authors.affiliation: Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Vesuna
authors.affiliation: Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.|Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Guus M
authors.initials: GM
authors.lastname: Bol
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.|Department of Oncology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.|Department of Oncology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA. vraman2@jhmi.edu.|Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. vraman2@jhmi.edu.|Department of Oncology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA. vraman2@jhmi.edu.
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D061986:MCF-7 Cells; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000378:metabolism
chemical_list: C000603512:3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one; D001381:Azepines; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases; C531550:olaparib
keywords: BRCA; Breast cancer; DDX3; DEAD box RNA helicase; DNA damage repair; PARP inhibitor