Cancer Cell Article Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient

cancer genetic alterations, studies defining the pathways deregulated in tumor progression and metastases are limited. LKB1 inactivation is found in up to 30 % of human NSCLCs, and Lkb1-deficient lung tumors in mice have a high penetrance of lymph node and distant metastases. Our analyses of primary and metastatic Lkb1-deficient mouse lung tumors have shown that progression to metastatic lung cancer is associated with unique gene and phosphoprotein signatures. In this work, we employ these signatures to design an effective, rational therapeutic strategy to treat Lkb1-deficient lung cancers.DOI 10.1016/j.ccr.2010.04.026 SUMMARY 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 acti-vated 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