Combinatorial strategy using protein kinase inhibitors and a cytotoxic compound for highly resistant glioblastoma cells : "in vitro studies"

Glioblastoma multiforme (GBM) is the most frequent and the most aggesssive malignant neoplasm of the human central nervous system (CNS), with a median survival of less than one year. These neoplasms are radio- and chemo-resistant, and are highly invasive, which renders their surgical resection inefficient. Because of the lack of efficiency of those conventional therapies, GBM patient prognosis has remained unchanged for the last forty years. Gene amplification and overexpression of the ErbB-related tyrosine-kinase receptor for epidermal growth factor (EGFR) are found in 40-50% of GBM, and correlate with progression of the disease and poor response to treatment. PKI-166 and AEE788 are small molecular weight protein kinase inhibitors (PKIs) of EGFR activity that can therefore potentially control progression of GBM. In fact, PKIs against ErbB receptors did not induce apoptosis on GBM cells in vitro. We further assessed a pro-apoptotic effect of anti-ErbB PKIs in the presence of the microtubule stabilizer and cytotoxic drug patupilone applied at suboptimal doses. Combination of AEE788 with patupilone led to a synergistic induction of apoptosis in 50% of glioma cell lines. In the remaining resistant lines, the simultaneous use of PKIs against downstream EGF signaling mediators Phosphatidylinositol-3 kinase (PI3K) and mitogeneactivated kinase/ERK kinase (MEK), Wortmannin and U0126, respectively, potentiated tumor cell apoptosis. The use of these particular drug combinations allows a novel approach for the treatment of glioblastoma patients.