Abstract：
:The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133(+) tumor-propagating cells isolated from primary GBM cell lines. We show that CD133(+) cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133(-) cells. Furthermore, CD133(+) cells exhibited an extended G2-M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133(+) cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133(+) cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Lerner RG,Grossauer S,Kadkhodaei B,Meyers I,Sidorov M,Koeck K,Hashizume R,Ozawa T,Phillips JJ,Berger MS,Nicolaides T,James CD,Petritsch CKdoi
10.1158/0008-5472.CAN-14-3689subject
Has Abstractpub_date
2015-12-15 00:00:00pages
5355-66issue
24eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-14-3689journal_volume
75pub_type
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