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Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive

tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of

JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic

tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of

TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting

metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The

combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic

BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and

metastasis, thereby supporting future clinical testing.

A Correction to this paper has been published: https://doi.org/10.1038/s41388-024-03046-9

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: A Cancer J Clin. 2020;70:7–30.

We would like to acknowledge the Massagué laboratory for gifting the 231-BoM and 231-BrM breast cancer cell lines and Dr. Dihua Yu for gifting the BT474-TtzmR cell line. We acknowledge

funding support for this project from NIH grants, R01NS087169 (HWL), T32CA079448 (RLC), R01NS087169-3S1 (HWL and SS), 1T32CA247819-01 (ATR), P30CA012197 (BP), 1R01CA228137-01A1 (HWL), as

well as, DoD grants, W81XWH-17-1-0044 (HWL), W81XWH-19-1-0072 (HWL), W81XWH-19-1-0753 (HWL), and W81XWH-20-1-0044 (HWL and JL).

Present address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-Bloomington, JH 308 1001 E. 3rd St., Bloomington, IN, 47405, USA

These authors contributed equally: Daniel Doheny, Sherona Sirkisoon

Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Daniel Doheny, Sherona Sirkisoon, Richard L. Carpenter, Noah Reeve Aguayo, Angelina T. Regua, Marlyn Anguelov, Sara G. Manore, Austin Arrigo, Sara Abu Jalboush, Grace L. Wong, Yang Yu, 

Calvin J. Wagner & Hui-Wen Lo

Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Michael Chan, Jimmy Ruiz, Alexandra Thomas, Roy Strowd & Hui-Wen Lo

Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA

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