title: Seribantumab, an Anti-ERBB3 Antibody, Delays the Onset of Resistance and Restores Sensitivity to Letrozole in an Estrogen Receptor-Positive Breast Cancer Model.
abstract: Heregulin-driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models. In this study, we evaluated the effects of seribantumab (MM-121), a heregulin-blocking anti-ERBB3 monoclonal antibody, alone and in combination with the aromatase inhibitor letrozole, on cell signaling and tumor growth in a preclinical model of postmenopausal estrogen receptor-positive (ER(+)) breast cancer. In vitro, heregulin treatment induced estrogen receptor phosphorylation in MCF-7Ca cells, and long-term letrozole-treated (LTLT-Ca) cells had increased expression and activation levels of EGFR, HER2, and ERBB3. Treatment with seribantumab, but not letrozole, inhibited basal and heregulin-mediated ERBB receptor phosphorylation and downstream effector activation in letrozole-sensitive (MCF-7Ca) and -refractory (LTLT-Ca) cells. Notably, in MCF-7Ca-derived xenograft tumors, cotreatment with seribantumab and letrozole had increased antitumor activity compared with letrozole alone, which was accompanied by downregulated PI3K/MTOR signaling both prior to and after the development of resistance to letrozole. Moreover, the addition of an MTOR inhibitor to this treatment regimen did not improve antitumor activity and was not well tolerated. Our results demonstrate that heregulin-driven ERBB3 signaling mediates resistance to letrozole in a preclinical model of ER(+) breast cancer, suggesting that heregulin-expressing ER(+) breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy.
authors: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors: Michael D
authors: MD
authors: Curley
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Gauri J
authors: GJ
authors: Sabnis
authors: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors: Lucia
authors: L
authors: Wille
authors: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors: Bambang S
authors: BS
authors: Adiwijaya
authors: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors: Gabriela
authors: G
authors: Garcia
authors: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors: Victor
authors: V
authors: Moyo
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Armina A
authors: AA
authors: Kazi
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Angela
authors: A
authors: Brodie
authors: Merrimack Pharmaceuticals, Cambridge, Massachusetts. gmacbeath@merrimackpharma.com.
authors: Gavin
authors: G
authors: MacBeath
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D000077289:Letrozole; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020890:Neuregulin-1 / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*; D010052:Ovariectomy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077289:Letrozole; D020890:Neuregulin-1; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D020893:Receptor, ErbB-3; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C000589319:seribantumab; C581292:ERBB3 protein, human