Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells

Abstract

The oncogenic epidermal growth factor receptor (EGFR) pathway triggers downstream phosphatidylinositol 3-kinase (PI3K)/RAS-mediated signaling cascades. In transgenic mice, glioblastoma cannot develop on single but only on simultaneous activation of the EGFR signaling mediators RAS and AKT. However, complete blockade of EGFR activation does not result in apoptosis in human glioblastoma cells, suggesting additional cross-talk between downstream pathways. Based on these observations, we investigated combination therapies using protein kinase inhibitors against EGFR, platelet-derived growth factor receptor, and mammalian target of rapamycin, assessing glioblastoma cell survival. Clinically relevant doses of AEE788, Gleevec (imatinib), and RAD001 (everolimus), alone or in combinations, did not induce glioblastoma cell apoptosis. In contrast, simultaneous inactivation of the EGFR downstream targets mitogen-activated protein/ extracellular signal-regulated kinase (ERK) kinase and PI3K by U0126 and wortmannin triggered rapid tumor cell death. Blocking EGFR with AEE788 in combination with sublethal concentrations of the microtubule stabilizer patupilone also induced apoptosis and reduced cell proliferation in glioblastoma cells, accompanied by reduced AKT and ERK activity. These data underline the critical role of the PI3K/AKT and the RAS/RAF/mitogenactivated protein/ERK kinase/ERK signaling cascades in the cell-intrinsic survival program of sensitive glioblastoma cell lines. We conclude that drug combinations, which down-regulate both ERK and protein kinase B/AKT activity, may prove effective in overcoming cell resistance in a subgroup of glioblastoma. [Mol Cancer Ther 2007; 6(2):773 -81]

Notch signaling in glioblastoma: a developmental drug target?

“…The drug needs to be harmless for healthy cells and to be able to pass the blood brain barrier to penetrate the tumor. Further, as previously shown in vitro [111,112], combinations of compounds that target non-redundant GBM pathways or with cytotoxic agents may synergize to induce GBM cell death. Such combinations that would include Notch signaling inhibitors are hoped will provide promising therapies to substantially improve patient outcomes.…”

The microtubule as a breast cancer target

“…First, phosphorylated MAPs negatively regulate microtubule stability because of their reduced binding affinity. Hence, disruption of signaling through the PI3K/Akt pathway seems to sensitize tumor cells selectively to microtubule inhibition [136,138,139]. The hypothesis that EGFRmediated activation of Akt may be more susceptible to targeting both microtubule and receptor is being tested in a clinical trial of ixabepilone alone or in combination with cetuximab as first-line therapy for advanced triple-negative breast cancer.…”

RAD001 offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer

“…The inhibition of rapamycin on mTOR induced the activation of its upstream receptor Akt and exhibited an enhanced resistance to inhibitor of mTOR, which had been confirmed both in the cancer cell lines and in patient tumors treated with RAD001 (8,(40)(41)(42)(43). There are many reports showing the effectiveness of the combinatorial therapy, in which mTOR inhibitor was combined with other kinase inhibitors, or chemotherapy and radiation treatment (24,(28)(29)(30)(44)(45)(46). The results suggested that the combinatorial anticancer therapy strategy was necessary when using the mTOR inhibitors as anti-tumor drugs.…”