Deciphering cellular states of innate tumor drug responses

ABSTRACT: Clinical drug resistance is one major concern in the treatment of human cancers, most of them being found resistant to therapy at the time of drug presentation. Deciphering the molecular mechanisms that contribute to such innate drug resistance should improve both the prediction of treatment failure and the development of new strategies to overcome resistance. Our study reports for the first time a systems approach toward understanding the in vivo cellular states of clinical samples collected from colorectal cancer (CRC) patients prior to their exposure to combined chemotherapy of folinic acid (FA), 5-fluorouracil (5-FU) and irinotecan (CPT-11). 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 which intrinsically differentiate, 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. Molecular interaction networks were 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. Keywords: Drug response

ORGANISM(S): Homo sapiens

PROVIDER: GSE3964 | GEO | 2006/03/01

SECONDARY ACCESSION(S): PRJNA94225

REPOSITORIES: GEO