Protein drug target activation homogeneity in the face of intra-tumor heterogeneity: implications for precision medicine

INTRODUCTION: Recent studies indicated tumors may be comprised of heterogeneous\r\nmolecular subtypes and incongruent molecular portraits may emerge if different\r\nareas of the tumor are sampled. This study explored the impact of intra-tumoral\r\nheterogeneity in terms of activation/phosphorylation of FDA approved drug targets\r\nand downstream kinase substrates.\r\nMATERIAL AND METHODS: Two independent sets of liver metastases from colorectal\r\ncancer were used to evaluate protein kinase-driven signaling networks within\r\ndifferent areas using laser capture microdissection and reverse phase protein\r\narray.\r\nRESULTS: Unsupervised hierarchical clustering analysis indicated that the\r\nsignaling architecture and activation of the MAPK and AKT-mTOR pathways were\r\nconsistently maintained within different regions of the same biopsy.\r\nIntra-patient variability of the MAPK and AKT-mTOR pathway were <1.06 fold\r\nchange, while inter-patients variability reached fold change values of 5.01.\r\nCONCLUSIONS: Protein pathway activation mapping of enriched tumor cells obtained \r\nfrom different regions of the same tumor indicated consistency and robustness\r\nindependent of the region sampled. This suggests a dominant protein pathway\r\nnetwork may be activated in a high percentage of the tumor cell population. Given\r\nthe genomic intra-tumoral variability, our data suggest that\r\nprotein/phosphoprotein signaling measurements should be integrated with genomic\r\nanalysis for precision medicine based analysis.