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

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INTRODUCTION TRAIL‐induced migration and invasion Lung cancer is the leading cause of cancer‐related mortality worldwide [1]. NSCLC accounts for 85% of all lung cancer cases. Although several attempts have been made to develop effective treatment strategies to combat lung cancer, still overall 5‐year prognosis is less than 15% in NSCLC [2]. Despite recent successes in sub‐populations of NSCLC patients using targeted agents, such as inhibitors of epidermal growth factor signaling (EGF) in patients with mutated EGF receptors, new therapies are urgently needed for improving treatment [3]. An attractive approach for the treatment of NSCLC is provided through the TRAIL receptors. TRAIL receptors are attractive targets as their stimulation selectively mediates apoptosis activation in tumor cells while sparing normal cells [4]. Apoptosis activation is mediated via two of five known TRAIL receptors, TRAIL‐R1 (DR4) and TRAIL‐R2 (DR5), whereas TRAIL‐R3 (DcR1) and TRAIL‐R4 (DcR2) are thought to encode non‐functional receptors, also named decoy receptors. A fifth receptor is osteoprotegerin that acts as a soluble receptor. Apoptosis activation occurs upon ligand‐induced TRAIL‐R1 or TRAIL‐R2 clustering leading to the assembly of the death‐inducing signaling complex (DISC). In the DISC, Fas‐associated protein with death domain (FADD) binds procaspase‐8 or ‐10 in order to produce active caspase‐8 subsequently leading to effector caspases activation and apoptosis [4]. Recombinant TRAIL preparations and TRAIL receptor specific agonistic antibodies have been produced that potently eradicate tumor cells of different origins, including NSCLC, and showed efficacy in various preclinical models [5]. Anti‐cancer action of TRAIL receptor targeted agents when applied as single agents, however, is frequently hampered by resistance in tumor cells. For example, approximately half of the NSCLC tumor cells are resistant to the apoptosis‐inducing effect of TRAIL unless applied in combination with various conventional or biological agents resulting in sensitive cells [5]. Thus, although currently clinical testing of TRAIL receptor targeted agents shows only moderate efficacy, there is optimism that combination strategies with other therapeutics will overcome resistance and increase therapeutic benefit. In contrast to its apoptosis‐inducing activity, TRAIL has been reported to activate non‐ apoptotic signaling. In resistant tumor cells TRAIL receptors have been reported to activate pro‐inflammatory (NF‐ĸB), pro‐survival (PI3K/Akt) and proliferation (mitogen activated protein kinases (MAPKs)) pathways [6]. Activation of these non‐apoptotic signaling pathways involves the recruitment of a number of proteins to the receptors, such as receptor‐interacting protein 1 (RIP1), TNF receptor associated factor 2 (TRAF2), TNF receptor type 1‐associated death domain (TRADD) and NEMO/IKK‐γ, thus forming secondary intracellular complexes [7;8]. The precise compositions and sequence of formation of the multiprotein complexes in which these factors reside are currently elusive. However, the death domain containing kinase RIP1 was shown to play a pivotal ‐ 61 ‐
Chapter 4 role in the activation of NF‐κB, JNK, p38 and ERK1/2 by TRAIL, and in the activation of necroptosis by TNF [9;10]. More recently TRAIL has also been implicated in the promotion of tumor cell invasion in pancreatic ductal adenocarcinoma and colorectal cancer models [11;12], further illustrating pro‐tumorigenic/ non‐canonical activity of TRAIL in resistant tumor cells. Clearly, the dual activity of TRAIL can hamper its clinical activity and delineating these unwanted effects is essential for developing strategies to revert them into pro‐apoptotic signals. Together, these considerations prompted us for a systematic evaluation of the nature of these non‐canonical TRAIL‐dependent pathways. In the present study we have examined the possible pro‐tumorigenic effects of TRAIL on NSCLC cells. Particularly we found that TRAIL induces migration and invasion of TRAIL‐ resistant NSCLC cells. A kinome profiling strategy was used to dissect underlying molecular mechanisms and the identified kinases were further examined for involvement in non‐canonical TRAIL signaling. Collectively, our results identified a novel TRAIL‐induced Src‐STAT3‐dependent tumor cell migratory pathway and imply enhanced therapeutic benefit of TRAIL therapy when combined with Src and PI3K/Akt inhibition. ‐ 62 ‐
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TRAIL-induced kinases activation an
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TRAIL‐induced kinases activation
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“In order to be irreplaceable one
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‐ 8 ‐
Page 11 and 12: Chapter 1 GENERAL INTRODUCTION Canc
Page 13 and 14: Chapter 1 OUTLINE OF THE THESIS As
Page 15 and 16: Chapter 1 Reference List 1. Jemal A
Page 17 and 18: Chapter 2 ABSTRACT Tumor necrosis f
Page 19 and 20: Chapter 2 INTRODUCTION The death li
Page 21 and 22: Chapter 2 In preclinical studies, a
Page 23 and 24: Chapter 2 Table 1| Summary of the k
Page 25 and 26: Chapter 2 proliferation could be pr
Page 27 and 28: Chapter 2 Figure 2. Canonical and n
Page 29 and 30: Chapter 2 associated with TRAIL res
Page 31 and 32: Chapter 2 adhesion molecules [109].
Page 33 and 34: Chapter 2 Reference List 1. Ashkena
Page 35 and 36: Chapter 2 37. Tolcher AW, Mita M, M
Page 37 and 38: Chapter 2 melanoma cells from TRAIL
Page 39 and 40: Chapter 2 and ERK pathways. Circula
Page 41 and 42: Chapter 3 ABSTRACT Tumor necrosis f
Page 43 and 44: Chapter 3 inhibitors and TRAIL rece
Page 45 and 46: Chapter 3 of amplification of the t
Page 47 and 48: Chapter 3 P38 and JNK have opposing
Page 49 and 50: Chapter 3 Figure 2 (continued). (e)
Page 51 and 52: Chapter 3 previously established H4
Page 53 and 54: Chapter 3 effect on TRAIL‐induced
Page 55 and 56: Chapter 3 induced apoptosis in H460
Page 59 and 60: Chapter 3 40. Domina AM, Vrana JA,
Page 61: Chapter 4 ABSTRACT Tumor necrosis f
Page 65 and 66: Chapter 4 the tip with a diameter o
Page 67 and 68: Chapter 4 RESULTS TRAIL induces a s
Page 69 and 70: Chapter 4 vehicle control or with 5
Page 71 and 72: Chapter 4 Non‐canonical TRAIL res
Page 73 and 74: Chapter 4 A549‐shRIP1 cells clear
Page 75 and 76: Chapter 4 Figure 7. Inhibition of S
Page 77 and 78: Chapter 4 DISCUSSION The TRAIL rece
Page 79 and 80: Chapter 4 Src‐independent mechani
Page 81 and 82: Chapter 4 variants. Cell Death Dis
Page 83 and 84: Chapter 4 ‐ 82 ‐
Page 85 and 86: Chapter 5 ABSTRACT TRAIL is an inte
Page 87 and 88: Chapter 5 targets and subsequent pr
Page 89 and 90: Chapter 5 RESULTS Synergistic activ
Page 91 and 92: Chapter 5 ng/ml TRAIL (Fig. 3B). Ap
Page 93 and 94: Chapter 5 by sub‐G1 levels in the
Page 95 and 96: Chapter 5 DISCUSSION In the present
Page 99 and 100: Chapter 5 ‐ 98 ‐
Page 101 and 102: Chapter 6 ABSTRACT TRAIL is a tumor
Page 103 and 104: Chapter 6 various stress stimuli [1
Page 105 and 106: Chapter 6 Subsequently, the membran
Page 107 and 108: Chapter 6 B H460 A549 Figure 1. Rep
Page 109 and 110: Chapter 6 TRAIL‐dependent cell de
Page 111 and 112: Chapter 6 B H460 A549 C Figure 4 (c
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Chapter 6 Figure 5 (continued). Mec
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Chapter 6 regulation and checkpoint
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Chapter 6 mechanism of immune evasi
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Chapter 7 ABSTRACT Thymidine phosph
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Chapter 7 Figure 1. Schematic overv
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Chapter 7 that was measured before
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Chapter 7 RESULTS TdR conversion to
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Chapter 7 dR is secreted from the c
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Chapter 7 Figure 4. Accumulation of
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Chapter 7 angiogenic properties. Ho
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Chapter 7 activity of enzymes. Natu
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Chapter 7 ‐ 134 ‐
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Chapter 8 SUMMARIZING DISCUSSION AN
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Chapter 8 Recently, various differe
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Chapter 8 in phase II clinical tria
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Chapter 8 Reference List 1. Herbst
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Chapter 8 ‐ 144 ‐
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Chapter 9 NEDERLANDSE SAMENVATTING
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Chapter 9 waargenomen. Het gebruik
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Chapter 9 CONCLUSIE Het activeren v
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zelfs na werktijden (lees 23:45) ko
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Verder wil ik ook dr. Eric Ronken b
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