Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC).
BACKGROUND
NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors.


METHODS
The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue.


RESULTS
There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents.


CONCLUSIONS
Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.
Glaysher
Sharon
S
Translational Oncology Research Centre, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK. sharonglaysher@googlemail.com
Yiannakis
Dennis
D
Gabriel
Francis G
FG
Johnson
Penny
P
Polak
Marta E
ME
Knight
Louise A
LA
Goldthorpe
Zoe
Z
Peregrin
Katharine
K
Gyi
Mya
M
Modi
Paul
P
Rahamim
Joe
J
Smith
Mark E
ME
Amer
Khalid
K
Addis
Bruce
B
Poole
Matthew
M
Narayanan
Ajit
A
Gulliford
Tim J
TJ
Andreotti
Peter E
PE
Cree
Ian A
IA
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged
D000970:Antineoplastic Agents