Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment

Paul T Winnard Jr; Farhad Vesuna; Guus M Bol; Kathleen L Gabrielson; Georgia Chenevix-Trench; Natalie D Ter Hoeve; Paul J van Diest; Venu Raman

doi:10.1016/j.canlet.2024.217260

Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment

Cancer Lett. 2024 Nov 1:604:217260. doi: 10.1016/j.canlet.2024.217260. Epub 2024 Sep 19.

Authors

Paul T Winnard Jr¹, Farhad Vesuna¹, Guus M Bol², Kathleen L Gabrielson³, Georgia Chenevix-Trench⁴, Natalie D Ter Hoeve⁵, Paul J van Diest⁶, Venu Raman⁷

Affiliations

¹ Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
² Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Medical Oncology, University Medical Center Utrecht Cancer Center, GA, Utrecht, the Netherlands.
³ Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4029, Australia.
⁵ Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, the Netherlands.
⁶ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, the Netherlands.
⁷ Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, the Netherlands; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. Electronic address: vraman2@jhmi.edu.

PMID: 39306228
DOI: 10.1016/j.canlet.2024.217260

Abstract

Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.

Keywords: Bone metastases; Breast cancer; DDX3; Intra-caudal artery injections; RK-33.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Azepines
Bone Neoplasms* / drug therapy
Bone Neoplasms* / secondary
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
DEAD-box RNA Helicases* / antagonists & inhibitors
DEAD-box RNA Helicases* / genetics
DEAD-box RNA Helicases* / metabolism
Drug Resistance, Neoplasm
Female
Humans
Imidazoles
Mice

Substances

DEAD-box RNA Helicases
DDX3X protein, human
Antineoplastic Agents
Ddx3x protein, mouse
3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one
Azepines
Imidazoles