title: Blocking NRG1 and other ligand-mediated Her4 signaling enhances the magnitude and duration of the chemotherapeutic response of non-small cell lung cancer.
abstract: Although standard chemotherapies are commonly used to treat most types of solid tumors, such treatment often results in inadequate response to, or relapse after, therapy. This is particularly relevant for lung cancer because most patients are diagnosed with advanced-stage disease and are treated with frontline chemotherapy. By studying the residual tumor cells that remain after chemotherapy in several in vivo non-small cell lung cancer models, we found that these cells have increased levels of human epidermal growth factor receptor (HER) signaling due, in part, to the enrichment of a preexisting NRG1(HI) subpopulation. Neuregulin 1 (NRG1) signaling in these models can be mediated by either the HER3 or HER4 receptor, resulting in the differential activation of downstream effectors. Inhibition of NRG1 signaling inhibits primary tumor growth and enhances the magnitude and duration of the response to chemotherapy. Moreover, we show that inhibition of ligand-mediated Her4 signaling impedes disease relapse in cases where NRG1 inhibition is insufficient. These findings demonstrate that ligand-dependent Her4 signaling plays an important role in disease relapse.
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Ganapati V
authors: GV
authors: Hegde
authors: Cecile C
authors: CC
authors: de la Cruz
authors: Cecilia
authors: C
authors: Chiu
authors: Navneet
authors: N
authors: Alag
authors: Gabriele
authors: G
authors: Schaefer
authors: Lisa
authors: L
authors: Crocker
authors: Sarajane
authors: S
authors: Ross
authors: David
authors: D
authors: Goldenberg
authors: Mark
authors: M
authors: Merchant
authors: Janet
authors: J
authors: Tien
authors: Lily
authors: L
authors: Shao
authors: Leslie
authors: L
authors: Roth
authors: Siao-Ping
authors: SP
authors: Tsai
authors: Scott
authors: S
authors: Stawicki
authors: Zhaoyu
authors: Z
authors: Jin
authors: Shelby K
authors: SK
authors: Wyatt
authors: Richard A D
authors: RA
authors: Carano
authors: Yanyan
authors: Y
authors: Zheng
authors: E Alejandro
authors: EA
authors: Sweet-Cordero
authors: Yan
authors: Y
authors: Wu
authors: Erica L
authors: EL
authors: Jackson
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology / Q000627:therapeutic use; D019898:Autocrine Communication / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D008024:Ligands; D020890:Neuregulin-1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4