MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade

  • Nat Commun. 2022 Jan 11;13(1):245. doi: 10.1038/s41467-021-27921-1.
Wei Wang   #  1 ,  Dong Han   #  1 ,  Qinbo Cai  1 ,  Tao Shen  1 ,  Bingning Dong  1  2 ,  Michael T Lewis  1  3 ,  Runsheng Wang  1 ,  Yanling Meng  1  4 ,  Wolong Zhou  1 ,  Ping Yi  1 ,  Chad J Creighton  2  3 ,  David D Moore  1  5 ,  Feng Yang  6
Affiliations
  • 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 2. Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 3. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 4. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
  • 5. Nutritional Sciences and Toxicology, University of California - Berkeley, Berkeley, CA, USA.
  • 6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 35017531 DOI: 10.1038/s41467-021-27921-1
Abstract

About 15-20% of breast Cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving Akt activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for Akt activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

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