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Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment
Paul T Winnard1, Farhad Vesuna1, Guus M Bol2
1Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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.
Insights
Targeting RNA helicase DDX3 with RK-33 effectively prevented bone metastasis in a mouse breast cancer model. This suggests DDX3 is a clinical target and RK-33 a potential treatment for bone metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Limited palliative treatment options exist for breast cancer bone metastasis.
- High DDX3 (RNA helicase) levels correlate with poor survival and bone metastasis in breast cancer patients.
Purpose of the Study:
- To investigate DDX3 as a therapeutic target in breast cancer bone metastasis.
- To evaluate the efficacy of the DDX3 inhibitor RK-33 in a mouse model.
Main Methods:
- Utilized a mouse model of breast cancer bone metastasis.
- Administered the small molecule DDX3 inhibitor RK-33.
- Generated and tested patient-derived and mouse-derived bone metastasis cell lines.
Main Results:
- RK-33 treatment completely prevented bone metastases in mice.
- RK-33-resistant cell lines remained sensitive to conventional chemotherapeutics.
- Differential DDX3 expression was found in patient bone metastasis samples.
Conclusions:
- DDX3 is a clinically relevant target for breast cancer bone metastasis.
- RK-33 demonstrates potential as a safe and effective treatment for this condition.
