title: p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks.
abstract: Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in the collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA; Department of Otolaryngology-Head and Neck Surgery, University of Virginia, Charlottesville, VA, USA. Electronic address: mja7z@virginia.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Axelrod
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA. Electronic address: vg6z@virginia.edu.
authors.forename: Vicki
authors.initials: V
authors.lastname: Gordon
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Virginia, Charlottesville, VA, USA. Electronic address: rem5d@virginia.edu.
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Mendez
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA. Electronic address: ssl4q@virginia.edu.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Leimgruber
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. Electronic address: mrc6j@virginia.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA. Electronic address: ers7g@virginia.edu.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sharlow
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Virginia, Charlottesville, VA, USA. Electronic address: mjj4e@virginia.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Jameson
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA. Electronic address: dgg3f@virginia.edu.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Gioeli
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA. Electronic address: mjw@virginia.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D007093:Imidazoles; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: Adaptive response; Fragile node; HER-family; MAP kinase; PI3 kinase; Signaling networks; p70S6 kinase