Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR) signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.

Figure 1

Survival Signalling. Hyperactive Receptor tyrosine kinases in GBMs, e.g., EGFR, PDGFR signal upon ligand binding or constitutive activation via Ras-MEK-ERK to mediate cell growth and angiogenesis and via PI3K/AKT to mediate survival. AKT phosphorylates multiple substrates that lead to release of survival factors or interference with the execution of apoptosis. Phosphoinositide-dependent kinase 1 (PDK1), phosphatidylinositol-3,4,5 triphosphate (PIP3), phosphoinositide-4,5 bisphosphate (PIP2), pro-apoptotic BCL-2-associated agonist of cell death (BAD), and Nuclear factor κB (NFκB).

Figure 2

PI3K crosstalks with MEK and mTOR pathways. In addition to their divergent signalling cascades, these pathways converge on mTOR and drive a negative feedback loop on AKT regulation. For GBMs, combined PI3K/AKT and Raf-MEK-ERK inhibition might be required to shutdown mTORC1 signalling and promote apoptosis, autophagy and prevent cell growth. Tuberosclerosis 1 (TSC1 and 2); Tumour necrosis factor alpha (TNFα), hypoxia inducible factor (HIF1α), regulated in development and DNA damage response 1 (REDD1), 4E-binding protein (4EBP).

Figure 3

Apoptosis Signalling network. The extrinsic apoptosis pathway is activated upon ligand binding to death receptors (TNFR1, Fas/CD95, DR4/5). This results in activation of a caspase cascade and eventually cleavage of both cytoplasmic and nuclear substrates. TNFR1 may promote survival signalling through activation of NFκB. The intrinsic pathway involves release of apoptotic proteins from the mitochondria, formation of the apoptosome and subsequently caspase activation. Members of the BCL-2 protein family are involved in regulation of the intrinsic apoptotic pathway. The extrinsic and the intrinsic pathways converge in a caspase cascade that results in cellular shrinkage, DNA fragmentation and eventually apoptosis. These pathways are highly deregulated in GBMs. Tumour necrosis factor receptor (TNFR), Tumour necrosis related apoptosis-inducing ligand (TRAIL), TNFR type 1-associated death domain protein (TRADD), Death receptor (DR), Fas-associated protein with death domain (FADD), TNFR associated factor (TRAF), Receptor interacting protein (RIP), FLICE-like inhibitory protein (FLIP), X-linked inhibitor of apoptosis protein (XIAP), Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), Inhibitor of κB (IκB), IκB kinases (IKKs), cytochrome c (Cyt c), Apoptotic protease activating factor 1 (Apaf-1).