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Ref Type Journal Article
PMID (30093561)
Authors Murali B, Ren Q, Luo X, Faget DV, Wang C, Johnson RM, Gruosso T, Flanagan KC, Fu Y, Leahy K, Alspach E, Su X, Ross MH, Burnette B, Weilbaecher KN, Park M, Mbalaviele G, Monahan JB, Stewart SA
Title Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 78 19 2018 10 01 5618-5630 Cancer Res
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ATI-450 ATI-450 0 0
CDD111 CDD111 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ATI-450 CDD-450|MK2Pi|Zunsemetinib ATI-450 is a small molecule that selectively inhibits MK2 (MAPKAPK2) activation by p38alpha (MAPK14), potentially leading to reduced metastatic tumor growth (PMID: 30093561, PMID: 29549113).
CDD111 SD-0006|SD0006|CDD-111 p38 MAPK Inhibitor (Pan) 3 CDD111 inhibits p38MAPK alpha (MAPK14), which potentially results in reduced metastatic tumor growth (PMID: 30093561).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References