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Cancer Res. 2018 Oct 1;78(19):5618-5630. doi: 10.1158/0008-5472.CAN-18-0234. Epub 2018 Aug 9.

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

Author information

1
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
2
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri.
3
Goodman Cancer Center, Department of Oncology, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
4
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
5
Aclaris Therapeutics, Inc., Saint Louis, Missouri.
6
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri. sheila.stewart@wustl.edu.
7
Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
8
ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.

Abstract

The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618-30. ©2018 AACR.

PMID:
30093561
PMCID:
PMC6168362
[Available on 2019-10-01]
DOI:
10.1158/0008-5472.CAN-18-0234

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