Candidate biomarkers of response to an experimental cancer drug identified through a large-scale RNA interference genetic screen.
OBJECTIVE
A major impediment in the optimal selection of cancer patients for the most effective therapy is the lack of suitable biomarkers that foretell the response of a patient to a given drug. In the present study, we have used large-scale RNA interference-based genetic screens to find candidate biomarkers of resistance to a new acyl sulfonamide derivative, R3200. This compound inhibits the proliferation of tumor cells in vitro and in vivo, but its mechanism of action is unknown.


METHODS
We used a large-scale RNA interference genetic screen to identify modulators of the efficacy of R3200. We searched for genes whose suppression in an in vitro cell system could cause resistance to the anticancer effects of R3200.


RESULTS
We report here that knockdown of either RBX1 or DDB1 causes resistance to the anticancer effects of R3200, raising the possibility that these two genes may have utility as biomarkers of response to this drug in a clinical setting. Interestingly, both RBX1 and DDB1 are part of an E3 ubiquitin ligase complex.


CONCLUSIONS
We propose that suppression of the activity of a RBX1 and DDB1-containing E3 ligase complex leads to the stabilization of certain proteins, the increased abundance of which is in turn responsible for resistance to R3200. Moreover, our data suggest that RBX1 and DDB1 could potentially be developed into biomarkers of resistance to acyl sulfonamide-based cancer drugs. This will require clinical validation in a series of patients treated with R3200.
Mullenders
Jasper
J
Division of Molecular Carcinogenesis, Center for Biomedical Genetics and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
von der Saal
Wolfgang
W
van Dongen
Miranda M W
MM
Reiff
Ulrike
U
van Willigen
Rogier
R
Beijersbergen
Roderick L
RL
Tiefenthaler
Georg
G
Klein
Christian
C
Bernards
René
R
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C547824:2-phenylethenesulfonic acid 2,4-dichlorobenzoylamide; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; C479529:RBX1 protein, human; C540494:RBX1 protein, mouse; D013449:Sulfonamides