Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment.
OBJECTIVE
Irinotecan (CPT11) treatment significantly improves the survival of colorectal cancer patients and is routinely used for the treatment of these patients, alone or in combination with other agents. However, only 20% to 30% of patients show an objective response to irinotecan, and there is great need for new molecular markers capable of identifying the subset of patients who are unlikely to respond.


METHODS
Here we used microarray analysis of a panel of 30 colorectal cancer cell lines and immunohistochemistry to identify and validate a new biomarker of response to irinotecan.


RESULTS
A good correlation was observed between irinotecan sensitivity and the expression of aprataxin (APTX), a histidine triad domain superfamily protein involved in DNA repair. Moreover, using an isogenic in vitro system deficient in APTX, we show that aprataxin directly regulates the cellular sensitivity to camptothecin, suggesting that it could be used to predict patient response to irinotecan. We constructed a tissue microarray containing duplicate tumor samples from 135 patients that received irinotecan for the treatment of advanced colorectal cancer. Immunohistochemical assessment of the tumor levels of aprataxin showed a significant association with treatment response and patient survival. Patients with low aprataxin had longer progression-free (9.2 versus 5.5 months; P = 0.03) and overall survival (36.7 versus 19.0 months; P = 0.008) than patients with high tumor aprataxin. No associations were found between coding APTX variants and aprataxin levels or camptothecin sensitivity.


CONCLUSIONS
These results show that aprataxin tumor levels can be used to identify patients with low probability of response to irinotecan-based therapy who are ideal candidates to receive treatment with alternative agents in an attempt to improve patient survival.
Dopeso
Higinio
H
Group of Molecular Oncology, Molecular Biology and Biochemistry Research Center, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Barcelona, Spain.
Mateo-Lozano
Silvia
S
Elez
Elena
E
Landolfi
Stefania
S
Ramos Pascual
Francisco Javier
FJ
Hernández-Losa
Javier
J
Mazzolini
Rocco
R
Rodrigues
Paulo
P
Bazzocco
Sarah
S
Carreras
Maria Josep
MJ
Espín
Eloy
E
Armengol
Manel
M
Wilson
Andrew J
AJ
Mariadason
John M
JM
Ramon Y Cajal
Santiago
S
Tabernero
Josep
J
Schwartz
Simo
S
Arango
Diego
D
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
C438188:APTX protein, human; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin