title: Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors.
abstract: In mice, Lkb1 deletion and activation of Kras(G12D) results in lung tumors with a high penetrance of lymph node and distant metastases. We analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles, and have identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. These studies revealed that SRC is activated in Lkb1-deficient primary and metastatic lung tumors, and that the combined inhibition of SRC, PI3K, and MEK1/2 resulted in synergistic tumor regression. These studies demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115 USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Klarisa
authors.initials: K
authors.lastname: Rikova
authors.forename: Autumn L
authors.initials: AL
authors.lastname: Jackson
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.forename: Christa L
authors.initials: CL
authors.lastname: Borgman
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Buttarazzi
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Sanofsky
authors.forename: Kate L
authors.initials: KL
authors.lastname: McNamara
authors.forename: Kathleyn A
authors.initials: KA
authors.lastname: Brandstetter
authors.forename: Zandra E
authors.initials: ZE
authors.lastname: Walton
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Silva
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Carla F
authors.initials: CF
authors.lastname: Kim
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Neil D
authors.initials: ND
authors.lastname: Hayes
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D023281:Genomics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins