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


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 array.


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.
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.|Department of Experimental Oncology, CRO-National Cancer Institute, Aviano, Italy.
Erika Maria
EM
Parasido
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Alessandra
A
Silvestri
Department of Pathology, CRO-National Cancer Institute, Aviano, Italy.
Vincenzo
V
Canzonieri
Department of Surgical Oncology, CRO-National Cancer Institute, Aviano, Italy.
Claudio
C
Belluco
Department of Pathology, Istituto Nazionale Tumori Regina Elena, Roma, Italy.
Maria Grazia
MG
Diodoro
Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
Massimo
M
Milione
Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
Flavia
F
Melotti
Department of Pathology, Sacred Heart Catholic University of Rome, Roma, Italy.
Ruggero
R
De Maria
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Lance
L
Liotta
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Emanuel F
EF
Petricoin
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Mariaelena
M
Pierobon
D000970:Antineoplastic Agents / Q000494:pharmacology; D016000:Cluster Analysis; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D057285:Precision Medicine / Q000379:methods; D011494:Protein Kinases / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D011494:Protein Kinases
intra-tumor heterogeneity; kinase signaling; laser capture microdissection; personalized therapy; reverse phase protein microarray