Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors.
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.
Carretero
Julian
J
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115 USA.
Shimamura
Takeshi
T
Rikova
Klarisa
K
Jackson
Autumn L
AL
Wilkerson
Matthew D
MD
Borgman
Christa L
CL
Buttarazzi
Matthew S
MS
Sanofsky
Benjamin A
BA
McNamara
Kate L
KL
Brandstetter
Kathleyn A
KA
Walton
Zandra E
ZE
Gu
Ting-Lei
TL
Silva
Jeffrey C
JC
Crosby
Katherine
K
Shapiro
Geoffrey I
GI
Maira
Sauveur-Michel
SM
Ji
Hongbin
H
Castrillon
Diego H
DH
Kim
Carla F
CF
García-Echeverría
Carlos
C
Bardeesy
Nabeel
N
Sharpless
Norman E
NE
Hayes
Neil D
ND
Kim
William Y
WY
Engelman
Jeffrey A
JA
Wong
Kwok-Kin
KK
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
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