title: Antibody targeting of HER2/HER3 signaling overcomes heregulin-induced resistance to PI3K inhibition in prostate cancer.
abstract: Dysregulated expression and/or mutations of the various components of the phosphoinositide 3-kinase (PI3K)/Akt pathway occur with high frequency in prostate cancer and are associated with the development and progression of castration resistant tumors. However, small molecule kinase inhibitors that target this signaling pathway have limited efficacy in inhibiting tumor growth, primarily due to compensatory survival signals through receptor tyrosine kinases (RTKs). Although members of the epidermal growth factor receptor (EGFR), or HER, family of RTKs are strongly implicated in the development and progression of prostate cancer, targeting individual members of this family such as EGFR or HER2 has resulted in limited success in clinical trials. Multiple studies indicate a critical role for HER3 in the development of resistance against both HER-targeted therapies and PI3K/Akt pathway inhibitors. In this study, we found that the growth inhibitory effect of GDC-0941, a class I PI3K inhibitor, is markedly reduced in the presence of heregulin. Interestingly, this effect is more pronounced in cells lacking phosphatase and tensin homolog function. Heregulin-mediated resistance to GDC-0941 is associated with reactivation of Akt downstream of HER3 phosphorylation. Importantly, combined blockade of HER2 and HER3 signaling by an anti-HER2/HER3 bispecific antibody or a mixture of anti-HER2 and anti-HER3 antibodies restores sensitivity to GDC-0941 in heregulin-treated androgen-dependent and -independent prostate cancer cells. These studies indicate that the combination of PI3K inhibitors with HER2/HER3 targeting antibodies may constitute a promising therapeutic strategy for prostate cancer.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Jayakumar S
authors.initials: JS
authors.lastname: Poovassery
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College of Medicine, College Station, TX.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Kang
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College of Medicine, College Station, TX.|Department of Biomedical Engineering, Texas A&M University, College Station, TX.
authors.forename: Dongyoung
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College of Medicine, College Station, TX.|Department of Biomedical Engineering, Texas A&M University, College Station, TX.
authors.forename: Raimund J
authors.initials: RJ
authors.lastname: Ober
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX.|Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College of Medicine, College Station, TX.|Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX.
authors.forename: E Sally
authors.initials: ES
authors.lastname: Ward
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D015151:Immunoblotting; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D020890:Neuregulin-1 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D000068878:Trastuzumab
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D007191:Indazoles; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D013449:Sulfonamides; D000068878:Trastuzumab; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
keywords: HER2; HER3; engineered antibody; heregulin; prostate cancer