Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53

Oncogene. 2021 May;40(21):3665-3679. doi: 10.1038/s41388-021-01784-8. Epub 2021 Apr 30.


Ovarian cancer (OvCA) remains one of the most devastating malignancies, but treatment options are still limited. We report that amphiregulin (AREG) can serve as an effective and safe pharmacological target in a syngeneic murine model. AREG is highly abundant in abdominal fluids of patients with advanced OvCa. In immunocompetent animals, depletion or overexpression of AREG respectively prolonged or shortened animal survival. A new antibody we generated in AREG-knockout mice recognized murine AREG and reproducibly prolonged animal survival in the syngeneic model. The underlying mechanism likely involves binding of wildtype p53 to AREG's promoter and autocrine activation of the epidermal growth factor receptor (EGFR), a step blocked by the antibody. Accordingly, depletion of p53 downregulated AREG secretion and conferred tolerance, whereas blocking an adaptive process involving CXCL1, which transactivates EGFR, might increase therapeutic efficacy. Consistent with these observations, analysis of OvCa patients revealed that high AREG correlates with poor prognosis of patients expressing wildtype TP53. In conclusion, clinical tests of the novel antibody are warranted; high AREG, normal TP53, and reduced CXCL1 activity might identify patients with OvCa who may derive therapeutic benefit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin / metabolism*
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Autocrine Communication
  • Biomarkers, Tumor / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Survival Rate
  • Tumor Suppressor Protein p53 / metabolism*


  • AREG protein, human
  • Amphiregulin
  • Antibodies, Monoclonal
  • Areg protein, mouse
  • Biomarkers, Tumor
  • TP53 protein, human
  • Tumor Suppressor Protein p53