Multiplexed protein signal pathway mapping identifies patients with rectal cancer that responds to neoadjuvant treatment.
BACKGROUND
Currently there is no reliable technique for predicting clinical or pathologic complete tumor response after radiochemotherapy (RCT) in patients with rectal cancer. We applied reverse phase protein microarray (RPMA) technology to find a signal pathway that may predict the response to preoperative treatment.


METHODS
Fifteen rectal cancer samples were collected during preoperative RCT. Seven patients had a good response to preoperative therapy (Mandard grade I-II) and 8 patients had a poor response (Mandard grade III-V). Using laser capture microdissection (LCM) and RPMA analysis, we measured the phosphorylation level of nearly 80 end points and analyzed the signaling pathways.


RESULTS
We identified 4 signaling proteins whose phosphorylation levels were significantly different (P < .05) between the good vs. poor responders; CHK2 and β-catenin were more highly phosphorylated in poor responders, whereas PDK1 and glycogen synthase kinase (GSK)-3α/β had lower phosphorylation levels in poor responders. Interestingly GSK-3α/β, β-catenin, and PDK1 are all present in the phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway.


CONCLUSIONS
Based on our results, we hypothesize that the activating state of the PI3K-AKT pathway can stratify patients who could benefit most from neoadjuvant treatment. Moreover, identification of theranostic targets has the potential to pinpoint new therapeutic strategies for the nonresponsive population.
Clinica Chirurgica II, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy. texaua@libero.it
Enzo
E
Mammano
Francesca
F
Galdi
Mariaelena
M
Pierobon
Emanuela
E
Tessari
Jianghong
J
Deng
Salvatore
S
Pucciarelli
Marco
M
Agostini
Francesco
F
De Marchi
Vincenzo
V
Canzonieri
Antonino
A
De Paoli
Claudio
C
Belluco
Lance
L
Liotta
Emanuel
E
Petricoin
Pierluigi
P
Pilati
Donato
D
Nitti
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D064447:Checkpoint Kinase 2; D005260:Female; D005500:Follow-Up Studies; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D010766:Phosphorylation; D011379:Prognosis; D040081:Protein Array Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
D014408:Biomarkers, Tumor; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051176:beta Catenin; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha