TY - JOUR
T1 - Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors
AU - Carretero, Julian
AU - Shimamura, Takeshi
AU - Rikova, Klarisa
AU - Jackson, Autumn L.
AU - Wilkerson, Matthew D.
AU - Borgman, Christa L.
AU - Buttarazzi, Matthew S.
AU - Sanofsky, Benjamin A.
AU - McNamara, Kate L.
AU - Brandstetter, Kathleyn A.
AU - Walton, Zandra E.
AU - Gu, Ting Lei
AU - Silva, Jeffrey C.
AU - Crosby, Katherine
AU - Shapiro, Geoffrey I.
AU - Maira, Sauveur Michel
AU - Ji, Hongbin
AU - Castrillon, Diego H.
AU - Kim, Carla F.
AU - García-Echeverría, Carlos
AU - Bardeesy, Nabeel
AU - Sharpless, Norman E.
AU - Hayes, Neil D.
AU - Kim, William Y.
AU - Engelman, Jeffrey A.
AU - Wong, Kwok Kin
N1 - Funding Information:
J.C. was a fellow of Spanish Ministry of Science and Innovation (MICINN) and Spanish Association against Cancer (AECC). T.S. was supported by the DF/HCC Claudia Adams Barr Program in Innovative Basic Cancer Research. K.-K.W. and J.A.E. are founders of Gatekeeper Therapeutics. This work was supported by Dana-Farber-Harvard Cancer Center Lung Cancer Specialized Program of Research Excellence (SPORE) grant P50 CA090578 (J.A.E. and K.-K.W.); U01CA141576 (K.-K.W., D.C., N.S. and N.B.) R01 AG2400401 (K.-K.W.), R01 CA122794 (K.-K.W.), R01 CA140594 (J.A.E. and K.-K.W.), 1RC2CA147940-01 (J.A.E. and K.-K.W.), K08 grant CA120060 (J.A.E.), R01CA137008 (J.A.E.), DF/HCC Gastrointestinal Cancer SPORE P50 CA127003 (J.A.E.); American Association for Cancer Research (J.A.E.); V Foundation (J.A.E.); American Cancer Society RSG-06-102-01-CCE (J.A.E.); and Ellison Foundation Scholar (J.A.E.). K.R., K.C., J.C.S. and T.-L.G. are employees of Cell Signaling Technology. C.G.-E. and S.-M.M. are employees of Novartis Institutes for Biochemical Research. J.A.E. receives research funding from Novartis. We thank H. Voelker for help in preparation of this manuscript.
PY - 2010/6/15
Y1 - 2010/6/15
N2 - In mice, Lkb1 deletion and activation of KrasG12D 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.
AB - In mice, Lkb1 deletion and activation of KrasG12D 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.
KW - CELLCYCLE
KW - SIGNALING
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U2 - 10.1016/j.ccr.2010.04.026
DO - 10.1016/j.ccr.2010.04.026
M3 - Article
C2 - 20541700
AN - SCOPUS:77953238558
SN - 1535-6108
VL - 17
SP - 547
EP - 559
JO - Cancer Cell
JF - Cancer Cell
IS - 6
ER -