title: Heregulin-ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells.
abstract: PI3K is frequently mutated in cancer and plays an important role in cell growth and survival. Heregulin (HRG)-mediated autocrine or paracrine signaling through the receptor tyrosine kinase ErbB3 potently activates the PI3K/AKT pathway and has been shown to mediate resistance to a wide variety of anticancer agents. Although PI3K functions downstream of HRG-ErbB3, it is unknown whether activating mutations in PI3K render HRG ineffective. If so, patients with PI3K mutations would not be expected to benefit from ErbB3-directed therapies. Here, we find that a subset of cell lines harboring activating PI3K mutations can be further growth-stimulated by HRG, and this effect is blocked by incubation with seribantumab (MM-121), a monoclonal anti-ErbB3 antibody. Although expression of mutant PI3K in wild-type PI3K cells frequently results in loss of HRG-stimulated growth, some cell lines continue to respond to HRG. In cell lines where HRG-stimulated growth is lost, this loss is invariably accompanied by a reduction in ErbB3 levels, a corresponding increase in basal phosphorylation levels of FOXO-family transcription factors, and a reduction in HRG-induced downstream signaling. Importantly, HRG-stimulated growth is partially rescued by re-expressing ErbB3. This response is blocked by seribantumab, indicating that ErbB3 levels rather than downstream signaling proteins limit HRG-stimulated growth in PI3K mutant cells. Overall, these results suggest that activating mutations in PI3K do not preclude potential benefit from ErbB3-directed therapy, but that it may be important to measure ErbB3 levels in patients with PI3K mutant cancers to determine if they would benefit.
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts. dyarar@merrimackpharma.com gmacbeath@merrimackpharma.com.
authors.forename: Defne
authors.initials: D
authors.lastname: Yarar
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lahdenranta
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: William
authors.initials: W
authors.lastname: Kubasek
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts. dyarar@merrimackpharma.com gmacbeath@merrimackpharma.com.
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D020893:Receptor, ErbB-3; C000589319:seribantumab