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Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

Oncogene volume 39, pages 6589–6605 (2020)Cite this article

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A Correction to this article was published on 27 April 2024

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Abstract

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.

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Fig. 1: JAK2 and SMO inhibitors synergize to suppress TNBC and HER2-positive/trastuzumab-resistant breast cancer in vitro.
Fig. 2: Simultaneous inhibition of JAK2-STAT3 and SMO signaling pathways suppress the cancer stem cell population.
Fig. 3: Co-treatment with JAK2 and SMO inhibitors suppresses the growth of TNBC tumors in vivo.
Fig. 4: Combined treatment with JAK2 and SMO inhibitors synergistically reduced TNBC metastasis in vivo.
Fig. 5: Co-treatment with JAK2 and SMO inhibitors suppresses the orthotopic growth and lung metastasis of HER2-positive/trastuzumab-resistant breast cancer in vivo.
Fig. 6: Combined treatment with JAK2 and SMO inhibitors synergize to reduce angiogenesis, tumor cell proliferation, and tumoral STAT3 activation of TNBC in vivo.
Fig. 7: JAK2 and SMO inhibitors synergize to reduce angiogenesis, tumor cell proliferation, and STAT3 activation of HER2-positive, trastuzumab-resistant breast cancer in vivo.

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Acknowledgements

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).

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  1. Richard L. Carpenter

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

  2. These authors contributed equally: Daniel Doheny, Sherona Sirkisoon

Authors and Affiliations

  1. 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

  2. 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

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

    Michael Chan

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

    Jimmy Ruiz & Alexandra Thomas

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

    Roy Strowd

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

    Jiayuh Lin

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Doheny, D., Sirkisoon, S., Carpenter, R.L. et al. Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene 39, 6589–6605 (2020). https://doi.org/10.1038/s41388-020-01454-1

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  • DOI: https://doi.org/10.1038/s41388-020-01454-1

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