Abstract
Immunotherapy based on T cell responses to the tumor is believed to involve killing of cancer cells by induction of apoptosis. The predominant mechanisms are death ligand-induced signaling mainly by TNF-related apoptosis-inducing ligand (TRAIL) mediated by CD4 T cells, monocytes and dendritic cells, and perforin/granzyme mediated apoptosis mediated by CD8 T cells and NK cells. Resistance against TRAIL involves loss of TRAIL death receptors and/or activation of the MEK and/or Akt signal pathways. Resistance to CD8 CTL responses also involves activation of the MEK and/or Akt pathways. Apoptosis induced by immune responses is regulated by the Bcl-2 family of proteins. Many reagents have been developed against the Bcl-2 antiapoptotic proteins and clinical trials combining them with immunotherapy are awaited. The second group of agents that regulate the Bcl-2 family of proteins are the signal pathway inhibitors. Clinical trials with inhibitors of RAS, RAF or MEK are in progress and would appear an exciting combination with immunotherapy. One of the main drivers of resistance to apoptosis are adaptive mechanisms that allow cancer cells to overcome endoplasmic reticulum (ER) stress. These adaptive mechanisms inhibit practically all known apoptotic pathways and create an acidic environment that may reduce infiltration of lymphocytes against the tumor. The signal pathway inhibitors may be effective against these adaptive processes but additional agents that target ER stress pathways are in development. In conclusion, combination of immunotherapy with agents that target antiapoptotic mechanisms in cancer cells offers a new approach that requires evaluation in clinical trials.
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References
Abraham RT, Eng CH (2008) Mammalian target of rapamycin as a therapeutic target in oncology. Expert Opin Ther Targets 12:209–222
Amaravadi R, Schuchter LM, McDermott DF, Kramer A, Giles L, Troxel AB, Medina CA, Nathanson KL, O’Dwyer PJ, Flaherty KT (2007) Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma. Proc Am Assoc Cancer Res 25:Abstract 8527
Andersen MH, Becker JC, Thor Straten P (2005) The antiapoptotic member of the Bcl-2 family Mcl-1 is a CTL target in cancer patients. Leukemia 19:484–485. doi:10.1038/sj.leu.2403621
Andersen MH, Jurgen CB, Thor Straten P (2005) Regulators of apoptosis: suitable targets for immune therapy of cancer. Nat Rev 4:399–409
Andersen MH, Reker S, Kvistborg P, Becker JC, Thor Straten P (2005) Spontaneous immunity against Bcl-xL in cancer patients. J Immunol 175:2709–2714
Andersen MH, Reker S, Becker JC, Thor Straten P (2004) The melanoma inhibitor of apoptosis protein: a target for spontaneous cytotoxic T cell responses. J Invest Dermatol 122:392–399
Andersen MH, Thor Straten P (2002) Survivin—a universal tumor antigen. Histol Histopathol 17:669–675
Ashkenazi A (2002) Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2:420–430
Ashkenazi A (2008) Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev 7:1001–1012
Balmanno K, Cook SJ (2009) Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ 16:368–377
Baltzis D, Pluquet O, Papadakis AI, Kasemi S, Qu LK, Koromilas AE (2007) The EIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of P53. J Biol Chem 282:31675–31687
Barbara JAJ, Van Ostade X, Lopez AF (1996) Tumour necrosis factor-alpha (TNF-α): the good, the bad and potentially very effective. Immunol Cell Biol 74:434–443
Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG (2006) Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 24:4738–4745
Bolitho P, Voskoboinik I, Trapani JA, Smyth MJ (2007) Apoptosis induced by the lymphocyte effector molecule perforin. Curr Opin Immunol 19:339–347
Brahimi-Horn MC, Pouyssegur J (2007) Harnessing the hypoxia-inducible factor in cancer and ischemic disease. Biochem Pharmacol 73:450–457
Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA (1997) Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7:679–689
Cartlidge RA, Thomas GR, Cagnol S, Jong KA, Molton SA, Finch AJ, McMahon M (2008) Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival. Pigment Cell Melanoma Res 21:534–544
Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403
Chen S, Dai Y, Harada H, Dent P, Grant S (2007) Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 67:782–791
Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656
Cossu F, Mastrangelo E, Milani M, Sorrentino G, Lecis D, Delia D, Manzoni L, Seneci P, Scolastico C, Bolognesi M (2009) Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2. Biochem Biophys Res Commun 378:162–167
De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C, Perdicchio M, Matarrese P, Lugini L, Nilsson A, Fais S (2007) Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 67:5408–5417
Dummer R, Robert C, Chapman PB, Sosman JA, Middleton M, Bastholt L, Kemsley K, Cantarini MV, Morris C, Kirkwood JM (2008) AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol ASCO Annual Meeting May 20 Suppl, Abstract 9033
Ehrhardt H, Fulda S, Schmid I, Hiscott J, Debatin KM, Jeremias I (2003) TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene 22:3842–3852
El-Deiry WS (2001) Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ 8:1066–1075
Fang J, Seki T, Maeda H (2009) Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev 61:290–302
Fang J, Nakamura H, Iyer AK (2007) Tumor-targeted induction of oxystress for cancer therapy. J Drug Target 15:475–486
Fecher LA, Cummings SD, Keefe MJ, Alani RM (2007) Toward a molecular classification of melanoma. J Clin Oncol 25:1606–1620
Feldman D, Koong AC (2007) Irestatin, a potent inhibitor of IRE1α and the unfolded protein response, is a hypoxia-selective cytotoxin and impairs tumor growth. 2007 ASCO annual meeting proceedings (post-meeting edition). J Clin Oncol 25:3514
Flaherty KT (2006) Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res 12:2366s–2370s
Fouladi M, Nicholson HS, Zhou T, Laningham F, Helton KJ, Holmes E, Cohen K, Speights RA, Wright J, Pollack IF, Children’s Oncology Group (2007) A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children’s Oncology Group study. Cancer 110:2535–2541
Franco AV, Zhang XD, Van Berkel E, Sanders JE, Zhang XY, Thomas WD, Nguyen T, Hersey P (2001) The Role of NF-κB in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells. J Immunol 166:5337–5345
Frew AJ, Lindemann RK, Martin BP, Clarke CJ, Sharkey J, Anthony DA, Banks KM, Haynes NM, Gangatirkar P, Stanley K, Bolden JE, Takeda K, Yagita H, Secrist JP, Smyth MJ, Johnstone RW (2008) Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist. Proc Natl Acad Sci USA 105:11317–11322
Fu Y, Li J, Lee AS (2007) GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res 67:3734–3740
Garlich JR, De P, Dey N, Su JD, Peng X, Miller A, Murali R, Lu Y, Mills GB, Kundra V, Shu HK, Peng Q, Durden DL (2008) A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 68:206–215
Gillespie S, Zhang XD, Hersey P (2005) Variable expression of protein kinase Cε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis. Mol Cancer Ther 4:668–676
Goda AE, Yoshida T, Horinaka M, Yasuda T, Shiraishi T, Wakada M, Sakai T (2008) Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole. Oncogene 27:3435–3445
Green DR (2006) At the gates of death. Cancer Cell 9:328–330
Green DR, Chipuk JE (2006) p53 and metabolism: inside the TIGAR. Cell 126:30–32
Green DR, Evan GI (2002) A matter of life and death. Cancer Cell 1:19–30
Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, Heim D, Larson RA, Branford S, Muller MC, Agarwal P, Gollerkeri A, Talpaz M (2007) Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109:4143–4150
Gyrd-Hansen M, Darding M, Miasari M, Santoro MM, Zender L, Xue W, Tenev T, da Fonseca PC, Zvelebil M, Bujnicki JM, Lowe S, Silke J, Meier P (2008) IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis. Nat Cell Biol 10:1309–1317
Hahnel PS, Thaler S, Antunes E, Huber C, Theobald M, Schuler M (2008) Targeting AKT signaling sensitizes cancer to cellular immunotherapy. Cancer Res 68:3899–3906
Haluska P, Dy GK, Adjei AA (2002) Farnesyl transferase inhibitors as anticancer agents. Eur J Cancer 38:1685–1700
Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermot A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O’Day S, Daud A, White M, Xia C, Patel K, Korkwood J, Keilholz U (2009) Results of a phase III randomized, placebo-controlled study of Sorafenib in combination with Carboplatin and Paclitaxel in second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. doi:10.1200/JCO.2007.15.7636
Hersey P (2002) Advances in the non-surgical treatment of melanoma. Expert Opin Investig Drugs 11:75–85
Hersey P, Zhang XD (2001) How melanoma cells evade TRAIL-induced apoptosis. Nat Rev Cancer 1:142–150
Hersey P, Zhang XD (2004) Immunotherapy of melanoma: principles. In: Thompson JF, Morton DL, Kroon BBR (eds) Textbook of melanoma. Martin Dunits/Taylor and Francis, London, pp 559–572
Hersey P, Zhang XD (2008) Adaptation to ER stress as a driver of malignancy and resistance to therapy in human melanoma. Pigment Cell Melanoma Res 21:358–367
Hetz CA (2007) ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage. Antioxid Redox Signal 9:2345–2355
Hipp MM, Hilf N, Walter S, Werth D, Kanz L, Weinschenk T, Singh H, Brossart P (2007) Sorafenib but not sunitinib affects the induction of immune responses. ASCO annual meeting proceedings part 1. J Clin Oncol 25:Abstract 3504
Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA 105:3005–3010
Hofmann UB, Voigt H, Andersen MH, Straten PT, Becker JC, Eggert AO (2009) Identification and characterization of surviving-derived H-2Kb-restricted CTL epitopes. Eur J Immunol 39:1419–1424
Holmstrom TH, Shmitz I, Soderstrom TS, Poukkula M, Johnson VL, Chow SC, Krammer PH, Eriksson JE (2000) MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly. EMBO J 19:5418–5428
Honma I, Kitamura H, Torigoe T, Takahashi A, Tanaka T, Sato E, Hirohashi Y, Masumori N, Tsukamoto T, Sato N (2009) Phase I clinical study of anti-apoptosis protein surviving-derived peptide vaccination for patients with advanced or recurrent urothelial cancer. Cancer Immunol Immunother (epub ahead of print)
Hu P, Han Z, Couvillon AD, Exton JH (2004) Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 279:49420–49429
Hunter AM, LaCasse EC, Korneluk RG (2007) The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12:1543–1568
Ihle NT, Powis G (2009) Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol Cancer Ther 8:1–9
Ivanov VN, Partridge MA, Johnson GE, Huang SX, Zhou H, Hei TK (2008) Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. Exp Cell Res 314:1163–1176
Ivanov VN, Hei TK (2006) Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. Exp Cell Res 312:4120–4138
Iwasa T, Okamoto I, Suzuki M, Nakahara T, Yamanaka K, Hatashita E, Yamada Y, Fukuoka M, Ono K, Nakagawa K (2008) Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines. Clin Cancer Res 14:6496–6504
Jiang CC, Chen LH, Gillespie S, Wang YF, Kiejda KA, Zhang XD, Hersey P (2007) Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis. Cancer Res 67:9750–9761
Jiang CC, Lucas K, Avery-Kiejda KA, Wade M, de Bock CE, Thorne RF, Allen J, Hersey P, Zhang XD (2008) Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon ER stress. Cancer Res 68:6708–6717
Jin Z, McDonald ER 3rd, Dicker DT, El-Deiry WS (2004) Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem 279:35829–35839
Jung EM, Park JW, Choi KS, Park JW, Lee HI, Lee KS, Kwon TK (2006) Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through CHOP-independent DR5 upregulation. Carcinogenesis 27:2008–2017
Kefford R, Millward M, Hersey P, Brady B, Graham M, Johson RG, Hannah AL (2007) Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma (Abstract 8558). Proc Am Soc Clin Oncol 25:486
Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H, Fleischer B, Trautwein C, Michalski C, Schulze-Bergkamen H, Friess H, Stremmel W, Krammer PH, Schirmacher P, Muller M (2006) Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. Cancer Res 66:7059–7066
Kim R, Emi M, Tanabe K, Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11:5–13
Kim S-H, Ricci MS, El-Deiry WS (2008) Mcl-1: a gateway to TRAIL sensitization. Cancer Res 68:2062–2064
Kono M, Dunn IS, Durda PJ, Butera D, Rose LB, Haggerty TJ, Benson EM, Kurnick JT (2006) Role of the mitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. Mol Cancer Res 4:779–792
Li J, Lee AS (2006) Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 6:45–54
Liang S, Sharma A, Peng HH, Robertson G, Dong C (2007) Targeting mutant (V600E) B-Raf in melanoma interrupts immunoediting of leukocyte functions and melanoma extravasation. Cancer Res 67:5814–5820
Lickliter JD, Cox J, McCarron J, Martinez NR, Schmidt CW, Lin H, Nieda M, Nicol AJ (2007) Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction. Br J Cancer 96:600–608
Lim JH, Lee ES, You HJ, Lee JW, Park JW, Chun YS (2004) Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion. Oncogene 23:9427–9431
Liu XM, Peyton KJ, Ensenat D, Wang H, Schafer AI, Alam J, Durante W (2005) Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival. J Biol Chem 280:72–877
Lopiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the P13K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11:32–50
Lu J, Bai L, Sun H, Nikolovska-Coleska Z, McEachern D, Qiu S, Miller RS, Yi H, Shangary S, Sun Y, Meagher JL, Stuckey JA, Wang S (2008) SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. Cancer Res 68:9384–9393
Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, Marra M, Lugini L, Logozzi M, Lozupone F, Federici C, Iessi E, Parmiani G, Arancia G, Belardelli F, Fais S (2004) Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 96:1702–1713
Luster TA, Carrell JA, McCormick K, Sun D, Humphreys R (2009) Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib. Mol Cancer Ther 8:292–302
Ma WW, Adjei AA (2009) Novel agents on the horizon for cancer therapy. CA Cancer J Clin 59:111–137
MacVicar GR, Kuzel TM, Curti BD, Poiesz B, Somer B, Greco FA, Gressler V, Brill K, Leopold L (2008) An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with hormone refractory prostate cancer (HRPC). ASCO annual meeting, May 20 Suppl, Abstract 16043. J Clin Oncol 26:2008
Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274
Mathupala SP, Parajuli P, Sloan AE (2004) Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery 55:1410–1419
Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–760
McDermott DF, Sosman JA, Hodi FS, Gonzalez R, Linette G, Richards J, Jakub JK, Beeram M, Patel K, Cranmer L (2007) Randomized phase II study of dacarbazine with or without sorafenib in patients with advanced melanoma. Proc Am Soc Clin Oncol 25:474s (Abstract 8511)
Meslin F, Thiery J, Richon C, Jalil A, Chouaib S (2007) Granzyme B-induced cell death involves induction of p53 tumor suppressor gene and its activation in tumor target cells. J Biol Chem 282:32991–32999
Mita MM, Britten CD, Poplin E, Tap WD, Carmona A, Yonemoto L, Wages DS, Bedrosian CL, Rubin EH, Tolcher AW (2008) Deforolimus trial 106—a phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669). J Clin Oncol 26:361–367
Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R, Comoglio PM (1993) Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. Br J Cancer 68:746–750
Nikiforov MA, Riblett M, Tang WH, Gratchouck V, Zhuang D, Fernandez Y, Verhaegen M, Varambally S, Chinnaiyan AM, Jakubowiak AJ, Soengas MS (2007) Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc Natl Acad Sci USA 104:19488–19493
Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ (2007) NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci USA 104:8953–8958
Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007:Issue 381, pe14
Panka DJ, Mano T, Suhara T, Walsh K, Mier JW (2001) Phosphatidylinositol 3-kinase/Akt activity regulates c-FLIP expression in tumor cells. J Biol Chem 276:6893–6896
Papadopoulos KP, Markman B, Tabernero J, Patnaik A, Heath EI, DeCillis A, Laird D, Aggarwal SK, Nguyen L, LoRusso PM (2008) A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL76, administered orally to patients (pts) with advanced solid tumors. J Clin Oncol 26:May 20 Supplement, Abstract 3510
Piesche M, Hildebrandt Y, Zetti F, Chapuy B, Schmitz M, Wulf G, Trumper L, Schroers R (2007) Identification of a promiscuous HLA DR-restricted T-cell epitope derived from the inhibitor of apoptosis is protein surviving. Hum Immunol 68:572–576
Pipkin ME, Lieberman J (2007) Delivering the kiss of death: progress on understanding how perforin works. Curr Opin Immunol 19:301–308
Pitter K, Bernal F, Labelle J, Walensky LD (2008) Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol 446:387–408
Psahoulia FH, Drosopoulos KG, Doubravska L, Andera L, Pintzas A (2007) Quercetin enhances TRAIL-mediated apoptosis is in colon cancer cells by inducing the accumulation of death receptors in lipid rafts. Mol Cancer Ther 6:2591–2599
Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O, Krausz T, Jagadeeswaran R, Salgia R (2007) c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res 13:2246–2253
Pyrko P, Schonthal AH, Hofman FM, Chen TC, Lee AS (2007) The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 67:9809–9816
Qu L, Huang S, Baltzis D, Rivas-Estilla A-M, Pluquet O, Hatzoglou M, Koumenis C, Taya Y, Yoshimura A, Koromilas AE (2004) Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β. Genes Dev 18:261–277
Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S, Henley A, Di-Stefano F, Ahmad Z, Guillard S, Bjerke LM, Kelland L, Valenti M, Patterson L, Gowan S, de Haven BA, Hayakawa M, Kaizawa H, Koizumi T, Ohishi T, Patel S, Saghir N, Parker P, Waterfield M, Workman P (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 67:5840–5850
Rosenthal R, Viehl CT, Guller U, Weber WP, Adamina M, Spagnoli GC, Heberer M, Zuber M (2008) Active specific immunotherapy phase III trials for malignant melanoma: systematic analysis and critical appraisal. J Am Coll Surg 207:95–105
Rottmann S, Wang Y, Nasoff M, Deveraux QL, Quon KC (2005) A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3beta/FBW7 loss of function. Proc Natl Acad Sci USA 102:15195–15200
Schimmer AD, O’Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, Yee K, Ravandi F, Giles F, Schuh A, Gupta V, Andreeff M, Koller C, Chang H, Kamel-Reid S, Berger M, Viallet J, Borthakur G (2008) A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 14:8295–8301
Semenza GL (2008) Tumor metabolism: cancer cells give and take lactate. J Clin Invest 118:3835–3837
Shaul YD, Seger R (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773:1213–1226
Shiraishi T, Yoshida T, Nakata S, Horinaka M, Wakada M, Mizutani Y, Miki T, Sakai T (2005) Tunicamycin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human prostate cancer cells. Cancer Res 65:6364–6370
Siddiquee KA, Gunning PT, Glenn M, Katt WP, Zhang S, Schroeck C, Sebti SM, Jove R, Hamilton AD, Turkson J (2007) An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem Biol 2:787–798
Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M (2006) Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther 5:1136–1144
Smalley KSM, Contractor R, Haass NK, Kulp AN, Atilla-Gokcumen GE, Williams DS, Bregman H, Flaherty KT, Soengas MS, Meggers E, Herlyn M (2007) An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res 67:209–217
Smalley KSM, Flaherty KT (2009) Integrating BRAF/MEK inhibitors into combination therapy for melanoma. Br J Cancer 100:431–435
Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203:1651–1656
Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK (2007) Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood 109:5430–5438
Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KSM, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim S-H, Schlessinger J, Zhang KYJ, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 105:3041–3046
Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68:3421–3428
Tsuruma T, Iwayama Y, Ohmura T, Katsuramaki T, Hata F, Furuhata T, Yamaguchi K, Kimura Y, Torigoe T, Toyota N, Yagihashi A, Hirohashi Y, Asanuma H, Shimozawa K, Okazaki M, Mizushima Y, Nomura N, Sato N, Hirata K (2008) Clinical and immunological evaluation of anti-apoptosis protein, surviving-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer. J Transl Med 6:24
van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399
VanBrocklin MW, Verhaegen M, Soengas MS, Holmen SL (2009) Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res 69:1985–1994
Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, Fairbrother WJ, Vucic D (2008) c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J Biol Chem 283:24295–24299
Vassilev LT (2006) MDM2 inhibitors for cancer therapy. Trends Mol Med 13:23–31
Vilimanovich U, Bumbasirevic V (2008) TRAIL induces proliferation of human glioma cells by c-FLIPL-mediated activation of ERK1/2. Cell Mol Life Sci 65:814–826
Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nature 6:940–952
Wahl ML, Owen JA, Burd R, Herlands RA, Nogai SS, Rodeck U, Berd D, Leeper DB, Owen CS (2002) Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol Cancer Ther 1:617–628
Walden P (2007) Therapeutic vaccination for the treatment of malignant melanoma. Recent Results Cancer Res 176:219–227
Wang JY, Wilcoxen KM, Nomoto K, Wu S (2007) Recent advances of MEK inhibitors and their clinical progress. Curr Top Med Chem 7:1364–1378
Wang L, Du F, Wang X (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133:693–703
Wang X, Chen W, Zeng W, Bai L, Tesfaigzi Y, Belinsky SA, Lin Y (2008) Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells. Mol Cancer Ther 7:1156–1163
Wang YF, Jiang CC, Kiejda KA, Gillespie S, Zhang XD, Hersey P (2007) Apoptosis induction in human melanoma cells by inhibition of MEK is caspase-independent and mediated by the Bcl-2 family members PUMA, Bim, and Mcl-1. Clin Cancer Res 13:4934–4942
Wang Z, Azmi AS, Ahmad A, Banerjee S, Wang S, Sarkar FH, Mohammad RM (2009) TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway. Cancer Res 69:2757–2765
Waterhouse NJ, Sedelies KA, Trapani JA (2006) Role of Bid-induced mitochondrial outer membrane permeabilization in granzyme B-induced apoptosis. Immunol Cell Biol 84:72–78
Willis SN, Adams JM (2005) Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17:617–625
Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DCS (2005) Proapoptotic Bak is sequestered by Mcl-1 and Bcl-XL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19:1294–1305
Yu JW, Shi Y (2008) FLIP and the death effector domain family. Oncogene 27:6216–6227
Zhang B, Zhang J, Tian Z (2008) Comparison in the effects of IL-2, IL-12, IL-15 and IFNα on gene regulation of granzymes of human NK cell line NK-92. Int Immunopharmacol 8:989–996
Zhang M, Fang X, Liu H, Guo R, Wu X, Li B, Zhu F, Ling Y, Griffith BN, Wang S, Yang D (2007) Bioinformatics-based discovery and characterization of an AKT-selective inhibitor 9-chloro-2-methylellipticinium acetate (CMEP) in breast cancer cells. Cancer Lett 252:244–258
Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P (2003) Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene 22:2869–2881
Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P (1999) Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 59:2747–2753
Zhang XD, Gillespie SK, Borrow JM, Hersey P (2004) The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Mol Cancer Ther 3:425–435
Zhang XD, Zhang XY, Gray CP, Nguyen T, Hersey P (2001) Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by Smac/DIABLO release from mitochondria. Cancer Res 61:7339–7348
Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Palmer AA, Zhang XD, Thompson JF, Bron LP, Hersey P (2005) Activation of the extracellular-signal related kinase (ERK) pathway in human melanoma. J Clin Pathol 58:1163–1169
Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P (2007) Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol 20:416–426
Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Screaton G, Hersey P (2006) Progression in melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Hum Pathol 37:1286–1294
Zobel K, Wang L, Varfolomeev E, Franklin MC, Elliott LO, Wallweber HJA, Okawa DC, Flygare JA, Vucic D, Fairbrother WJDK (2006) Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs. ACS Chem Biol 1:525–533
Zou W, Chen S, Liu X, Yue P, Sporn MB, Khuri FR, Sun S-Y (2007) c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid Methyl-2-Cyano-3, 12-Dioxooleana-1, 9-Dien-28-Oate (CDDO-Me) in human lung cancer cells. Cancer Biol Ther 6:1614–1620
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Hersey, P., Zhang, X.D. Treatment combinations targeting apoptosis to improve immunotherapy of melanoma. Cancer Immunol Immunother 58, 1749–1759 (2009). https://doi.org/10.1007/s00262-009-0732-5
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DOI: https://doi.org/10.1007/s00262-009-0732-5