towards improved death receptor targeted therapy for ... - TI Pharma

Introduction
clinical Phase I/II studies in different tumor types. Phase I studies have shown that
patients tolerate recombinant TRAIL (Apo2L/dulanerim) as well as agonistic antibodies
quite well [9].
TRAIL can bind to five different receptors, the death receptors, TRAIL‐R1 (DR4) and TRAIL‐
R2 (DR5), the decoy receptors TRAIL‐R3 (DcR1) and TRAIL‐R4 (DcR2), and the soluble
receptor osteoprotegerin (OPG) [10]. TRAIL activates the extrinsic pathway by binding to
TRAIL‐R1 and TRAIL‐R2. The death inducing signaling complex (DISC) consisting of FADD
and caspase‐8 is than formed, leading to caspase‐8 and caspase‐3 activation followed by
apoptosis. Caspase‐8 can also cleave the pro‐apoptotic Bcl‐2 family member Bid into tBid,
which in turn results in activation of other pro‐apoptotic family members, such as BAX or
BAK. This leads to the induction of mitochondrial activator outer membrane
permeabilization (MOMP) and release of cytochrome c and Smac/Diablo in the cytosol,
resulting in the activation of apoptosis through the intrinsic pathway that involves
caspases‐9 and ‐3 [11;12].
However, in addition to apoptosis induction that can be regarded as the canonical route
of TRAIL signaling an increasing number of studies have shown that TRAIL can also
activate diverse other intracellular non‐canonical signaling pathways in tumor cells. These
include mitogen activated protein kinases (MAPKs), phosphoinositide 3‐kinase (PI3K) and
Akt and nuclear factor κB (NF‐κB) that can enhance cell survival, cell proliferation and
even migration/ invasion of tumor cells, thus possibly stimulating tumorigenesis [13;14].
Moreover, a large number of cancer cells, especially the highly malignant ones, are
resistant to TRAIL‐induced apoptosis [15]. Some cancer cells that were initially sensitive to
TRAIL can also develop resistance. TRAIL resistance is related to alterations at different
points in the signaling pathway, mutations in the death receptors, inhibition of active DISC
formation by cFLIP or more downstream by overexpression of anti‐apoptotic proteins
amongst others XIAP and Bcl‐2 family members. The activation of the survival pathways
aforementioned can also counteract the apoptotic effect of TRAIL. To circumvent TRAIL
resistance and to increase the efficacy of this molecule, TRAIL can be combined with other
anti‐cancer agents, such as kinase inhibitors, radiation and chemotherapy (see for
extensive overview of TRAIL sensitizing strategies in lung cancer [16]).
The aim of the research described in this thesis is to obtain more knowledge of the
molecular mechanisms governing TRAIL resistance in NSCLC, in particular the role of
kinases herein. In addition, we have explored several combination treatments for
enhancing TRAIL efficacy. Ultimately, the work may lead to the identification of novel
predictive markers and therapeutic approaches for optimizing TRAIL‐based therapies.
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