Abstract
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.
Highlights
A humanized antibody against vascular endothelial growth factor (VEGF), bevacizumab, improved progression-free survival of patients with therapy-resistant ovarian cancer (OvCa), which led to clinical approval of the treatment [14]
We assumed that epidermal growth factor receptor (EGFR) ligands, especially AREG and EREG, which are frequently co-expressed in carcinomas [15], might offer similar treatment opportunities
ELISA-based analysis of ascites fluids, which we collected from 78 patients with OvCa who were pre-treated with chemotherapy, revealed that both VEGF and AREG were abundantly expressed in most patients, but EREG was detectable only in very few samples (Fig. 1A)
Summary
The high mortality of ovarian cancer (OvCa), which is directly associated with disseminated peritoneal metastasis, is attributed to delayed diagnosis and the fact that treatment has only moderately changed since the late 1990s [1]. Because the EGF and neuregulin (NRG) families of growth factors act as major mitogens of the ovarian epithelium, they might present an important node of intervention. A screen for potential “addicting oncogenes” using RNA interference found that an autocrine loop involving NRG1 operates in a subset of OvCa [3]. While none of the NRGs binds with epidermal growth factor receptor (EGFR), amphiregulin (AREG), epiregulin (EREG), and epigen bind to EGFR with relatively low affinity [4]. We previously identified AREG as an abundant and essential growth factor of OvCa [5]. The list includes chronic inflammation [6], treatment with chemotherapy [5], and expression of either the wildtype [7] or the mutant form of p53 [8]
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