Deciphering cellular states of innate tumor drug responses.
BACKGROUND
The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment.


RESULTS
Transcriptional profiles of clinical samples collected from CRC patients prior to their exposure to a combined chemotherapy of folinic acid, 5-fluorouracil and irinotecan were established using microarrays. Vigilant experimental design, power simulations and robust statistics were used to restrain the rates of false negative and false positive hybridizations, allowing successful discrimination between drug resistance and sensitivity states with restricted sampling. A list of 679 genes was established that intrinsically differentiates, for the first time prior to drug exposure, subsequently diagnosed chemo-sensitive and resistant patients. Independent biological validation performed through quantitative PCR confirmed the expression pattern on two additional patients. Careful annotation of interconnected functional networks provided a unique representation of the cellular states underlying drug responses.


CONCLUSIONS
Molecular interaction networks are described that provide a solid foundation on which to anchor working hypotheses about mechanisms underlying in vivo innate tumor drug responses. These broad-spectrum cellular signatures represent a starting point from which by-pass chemotherapy schemes, targeting simultaneously several of the molecular mechanisms involved, may be developed for critical therapeutic intervention in CRC patients. The demonstrated power of this research strategy makes it generally applicable to other physiological and pathological situations.
Array s/IMAGE, Genexpress, Functional Genomics and Systems Biology for Health, LGN-UMR 7091-CNRS and Pierre and Marie Curie University, Paris VI, Villejuif, France.
Esther
E
Graudens
Virginie
V
Boulanger
Cindy
C
Mollard
Régine
R
Mariage-Samson
Xavier
X
Barlet
Guilaine
G
Grémy
Christine
C
Couillault
Malika
M
Lajémi
Dominique
D
Piatier-Tonneau
Patrick
P
Zaborski
Eric
E
Eveno
Charles
C
Auffray
Sandrine
S
Imbeaud
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001706:Biopsy; D017322:Clinical Trials, Phase II as Topic; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012984:Software
D000970:Antineoplastic Agents