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|Ref Type||Journal Article|
|Authors||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 CK|
|Title||Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells.|
|Date||2015 Dec 15|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E||glioblastoma||decreased response||PD-0325901||Preclinical - Cell culture||Actionable||In a preclinical study, a glioblastoma cell line harboring BRAF V600E demonstrated a decreased response to treatment with PD-0325901, demonstrating increased viability of CD133 positive cells in culture (PMID: 26573800).||26573800|
|BRAF V600E||glioblastoma||decreased response||PLX4720||Preclinical - Cell line xenograft||Actionable||In a preclinical study, a glioblastoma cell line harboring BRAF V600E demonstrated a decreased response to treatment with PLX4720, demonstrating increased viability of CD133 positive cells in culture and in xenograft models (PMID: 26573800).||26573800|
|BRAF V600E||glioblastoma||sensitive||BI2536||Preclinical - Cell culture||Actionable||In a preclinical study, a glioblastoma cell line harboring BRAF V600E demonstrated sensitivity to BI2536 in culture (PMID: 26573800).||26573800|
|BRAF V600E||glioblastoma||sensitive||BI2536 + PLX4720||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of BI 2536 and PLX4720 resulted in suppression of downstream signaling, increased apoptotic activity, inhibition of cell proliferation, and tumor growth suppression in glioblastoma cell line xenograft models harboring BRAF V600E (PMID: 26573800).||26573800|