Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy.
Platinum-based chemotherapeutic drugs are front-line therapies for the treatment of non-small cell lung cancer. However, intrinsic drug resistance limits the clinical efficacy of these agents. Recent evidence suggests that loss of the translesion polymerase, Polζ, can sensitize tumor cell lines to cisplatin, although the relevance of these findings to the treatment of chemoresistant tumors in vivo has remained unclear. Here, we describe a tumor transplantation approach that enables the rapid introduction of defined genetic lesions into a preclinical model of lung adenocarcinoma. Using this approach, we examined the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. In the presence of reduced levels of Rev3, an essential component of Polζ, tumors exhibited pronounced sensitivity to cisplatin, leading to a significant extension in overall survival of treated recipient mice. Additionally, treated Rev3-deficient cells exhibited reduced cisplatin-induced mutation, a process that has been implicated in the induction of secondary malignancies following chemotherapy. Taken together, our data illustrate the potential of Rev3 inhibition as an adjuvant therapy for the treatment of chemoresistant malignancies, and highlight the utility of rapid transplantation methodologies for evaluating mechanisms of chemotherapeutic resistance in preclinical settings.
The Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jason
J
Doles
Trudy G
TG
Oliver
Eleanor R
ER
Cameron
Gerald
G
Hsu
Tyler
T
Jacks
Graham C
GC
Walker
Michael T
MT
Hemann
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D002945:Cisplatin; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53; C425929:DNA polymerase zeta; C495971:Hras protein, mouse; C486862:REV3L protein, mouse