Inhibition of the stromal p38MAPK/MK2 pathway limits breast cancer metastases and chemotherapy-induced bone loss

Bhavna Murali, Qihao Ren, Xianmin Luo, Douglas V. Faget, Chun Wang, Radia Marie Johnson, Tina Gruosso, Kevin C. Flanagan, Yujie Fu, Kathleen Leahy, Elise Alspach, Xinming Su, Michael H. Ross, Barry Burnette, Katherine N. Weilbaecher, Morag Park, Gabriel Mbalaviele, Joseph B. Monahan, Sheila A. Stewart

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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. p38MAPKa 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 p38MAPKa could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKa 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 p38MAPKa 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.

Original languageEnglish
Pages (from-to)5618-5630
Number of pages13
JournalCancer research
Volume78
Issue number19
DOIs
StatePublished - Oct 1 2018

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