title: ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas.
abstract: ERBB3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI3K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen-inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI3K-AKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFR(L858R)-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3-independent activation of the PI3K pathway by mutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications.
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.affiliation: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Pang-Dian
authors.initials: PD
authors.lastname: Fan
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Amlak
authors.initials: A
authors.lastname: Bantikassegn
authors.affiliation: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Udayan
authors.initials: U
authors.lastname: Guha
authors.affiliation: Department of Veterinary Pathobiology and Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas.
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.affiliation: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York. katerina.politi@yale.edu.
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human