Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors
- Carretero, Julian
- Shimamura, Takeshi
- Rikova, Klarisa
- Jackson, Autumn L.
- Wilkerson, Matthew D.
- Borgman, Christa L.
- Buttarazzi, Matthew S.
- Sanofsky, Benjamin A.
- McNamara, Kate L.
- Brandstetter, Kathleyn A.
- Walton, Zandra E.
- Gu, Ting-Lei
- Silva, Jeffrey C.
- Crosby, Katherine
- Shapiro, Geoffrey I.
- Maira, Sauveur-Michel
- Ji, Hongbin
- Castrillon, Diego H.
- Kim, Carla F.
- García-Echeverría, Carlos
- Bardeesy, Nabeel
- Sharpless, Norman E.
- Hayes, Neil D.
- Kim, William Y.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
DOIAbstract
SummaryIn 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
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