Abstract：
:Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide, but the disease inevitably recurs in a drug-resistant form after initial treatment. Here, we report that in GBM cells, even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sensitivity. RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of temozolomide resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress temozolomide-induced tumor regression. Using The Cancer Genome Atlas to analyze mRNA expression patterns in tumors from temozolomide-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial temozolomide therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades temozolomide sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of temozolomide resistance and argue that MMR activity offers a predictive marker for initial therapeutic response to temozolomide treatment.
journal_name
Cancer Resjournal_title
Cancer researchauthors
McFaline-Figueroa JL,Braun CJ,Stanciu M,Nagel ZD,Mazzucato P,Sangaraju D,Cerniauskas E,Barford K,Vargas A,Chen Y,Tretyakova N,Lees JA,Hemann MT,White FM,Samson LDdoi
10.1158/0008-5472.CAN-14-3616subject
Has Abstractpub_date
2015-08-01 00:00:00pages
3127-38issue
15eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-14-3616journal_volume
75pub_type
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