INTRODUCTION: Recent studies indicated tumors may be comprised of heterogeneous
molecular subtypes and incongruent molecular portraits may emerge if different
areas of the tumor are sampled. This study explored the impact of intra-tumoral
heterogeneity in terms of activation/phosphorylation of FDA approved drug targets
and downstream kinase substrates.
MATERIAL AND METHODS: Two independent sets of liver metastases from colorectal
cancer were used to evaluate protein kinase-driven signaling networks within
different areas using laser capture microdissection and reverse phase protein
RESULTS: Unsupervised hierarchical clustering analysis indicated that the
signaling architecture and activation of the MAPK and AKT-mTOR pathways were
consistently maintained within different regions of the same biopsy.
Intra-patient variability of the MAPK and AKT-mTOR pathway were <1.06 fold
change, while inter-patients variability reached fold change values of 5.01.
CONCLUSIONS: Protein pathway activation mapping of enriched tumor cells obtained
from different regions of the same tumor indicated consistency and robustness
independent of the region sampled. This suggests a dominant protein pathway
network may be activated in a high percentage of the tumor cell population. Given
the genomic intra-tumoral variability, our data suggest that
protein/phosphoprotein signaling measurements should be integrated with genomic
analysis for precision medicine based analysis.
- intra-tumor heterogeneity
- kinase signaling
- laser capture microdissection
- personalized therapy
- reverse phase protein microarray