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

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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NEGATIVE BREAST CANCER STEM CELLS AND CHEMOTHERAPY-RESISTANT DISEASE Article Open access 03 August 2021 P70S6K/AKT DUAL INHIBITOR DIACC3010 IS EFFICACIOUS IN PRECLINICAL MODELS OF GASTRIC

CANCER ALONE AND IN COMBINATION WITH TRASTUZUMAB Article Open access 25 September 2023 TARGETING TRANSCRIPTION OF _MCL-1_ SENSITIZES _HER2_-AMPLIFIED BREAST CANCERS TO HER2 INHIBITORS

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multiple resistance pathways. Nat Med. 2011;17:461–9. Article  PubMed  Google Scholar  Download references 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). AUTHOR INFORMATION Author notes * 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 * These authors contributed equally: Daniel Doheny, Sherona Sirkisoon AUTHORS AND AFFILIATIONS

* 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 Michael Chan * Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA Jimmy Ruiz & Alexandra

Thomas * Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA Roy Strowd * Department of Biochemistry and Molecular Biology, University of Maryland

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