Do High MAPK4 Expression Levels Reduce the Sensitivity of TNBC to PI3K Blockade?

By: Julia Fiederlein
Posted: Friday, March 4, 2022

Alterations in the PI3K pathway are frequently identified in patients with triple-negative breast cancer (TNBC); however, according to Feng Yang, PhD, of Baylor College of Medicine, Houston, and colleagues, the therapeutic benefits of PI3K inhibitors are limited in this population. The results of an analysis, which were published in Nature Communications, suggested that targeting MAPK4 in the large subset of patients with high expression levels of this oncogenic kinase may repress growth and sensitize tumors to PI3K blockade.

“Altogether, our findings suggest a new therapeutic opportunity for triple-negative breast cancer based on MAPK4 expression, perhaps including a combination of inhibitors to help control cancer growth,” Dr. Yang stated in an institutional press release. “Future studies will help clarify this idea.”

The investigators conducted in vivo experiments using mice and several laboratory assessments to analyze the biologic mechanisms underlying the lack of efficacy of PI3K inhibitors. MAPK4 was found to be highly expressed in a large subset of triple-negative breast cancer; according to the investigators, this expression may be critical for driving AKT activation independent of PI3K and promoting triple-negative breast cancer cell and xenograft growth. The ability of MAPK4 to bypass PI3K and directly activate AKT suggests that elevated MAPK4 expression levels may reduce tumor sensitivity to PI3K inhibition. Thus, according to the investigators, repressing MAPK4 may sensitize triple-negative breast cancer cells and xenografts to PI3K blockade.

Disclosure: For full disclosures of the study authors, visit nature.com.

Nature Communications

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