title: Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions.
abstract: Apoptosis is a metazoan process of controlled cell elimination that plays critical roles in embryonic development and adult tissue homeostasis. Apoptosis dysregulation contributes to several important diseases, including cancer. Two distinct yet interconnected signaling pathways control apoptosis by activating a core intracellular machinery of death proteases called caspases. The intrinsic apoptotic pathway engages caspases via members of the BCL-2 protein family and the mitochondria in reaction to severe cellular damage or stress. The extrinsic pathway activates caspases via cell-surface death receptors, which respond to cognate death ligands expressed on immune-effector cells. Tumor cells can acquire various apoptosis-evasion mechanisms; nevertheless, the transformed state of these cells makes them uniquely susceptible to apoptosis reactivation if resistance is circumvented. Molecular approaches to reengage the apoptotic pathways in cancer have been underway for over two decades. Gratifyingly, BCL-2 antagonists - which drive the intrinsic pathway - are beginning to bear clinical fruit. In contrast, clinical attempts to stimulate the extrinsic pathway with proapoptotic receptor agonists (PARAs) have been disappointing, despite compelling preclinical efficacy with this class of agents. Here, I discuss some of the possible reasons for this translational discrepancy and suggest strategies to overcome it with the next generation of PARAs.
authors: Avi
authors: A
authors: Ashkenazi
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases
references: Nat Rev Cancer. 2008 Oct;8(10):782-98
references: 18813321
references: J Clin Invest. 2008 Jun;118(6):1979-90
references: 18523647
references: Nat Immunol. 2009 Apr;10(4):348-55
references: 19295631
references: Cell. 2009 May 15;137(4):721-35
references: 19427028
references: Clin Cancer Res. 2010 Mar 15;16(6):1701-8
references: 20197482
references: Curr Opin Cell Biol. 2010 Dec;22(6):837-44
references: 20813513
references: Cancer Cell. 2011 Jan 18;19(1):101-13
references: 21251615
references: J Clin Oncol. 2011 Nov 20;29(33):4442-51
references: 22010015
references: Cancer Cell. 2012 Jul 10;22(1):80-90
references: 22789540
references: Mol Cancer Ther. 2012 Nov;11(11):2541-6
references: 22914439
references: Mol Cell. 2012 Dec 28;48(6):888-99
references: 23142077
references: Mol Cancer Ther. 2013 Dec;12(12):2735-47
references: 24101228
references: Mol Cell. 2014 Jun 19;54(6):987-98
references: 24882208
references: Science. 2014 Jul 4;345(6192):98-101
references: 24994655
references: Cancer Cell. 2014 Aug 11;26(2):177-89
references: 25043603
references: Mol Cell. 1999 Oct;4(4):563-71
references: 10549288
references: J Immunother. 2000 Jul-Aug;23(4):505-6
references: 10916761
references: Nat Med. 2001 Apr;7(4):383-5
references: 11283636
references: Nat Rev Cancer. 2002 Jun;2(6):420-30
references: 12189384
references: Immunity. 1995 Dec;3(6):673-82
references: 8777713
references: J Biol Chem. 1996 May 31;271(22):12687-90
references: 8663110
references: Cell. 1997 Feb 7;88(3):355-65
references: 9039262
references: Science. 1998 Aug 28;281(5381):1305-8
references: 9721089
references: Curr Opin Immunol. 1998 Oct;10(5):545-51
references: 9794832
references: Nat Med. 1999 Feb;5(2):157-63
references: 9930862
references: Annu Rev Immunol. 1999;17:331-67
references: 10358762
references: J Clin Invest. 1999 Jul;104(2):155-62
references: 10411544
references: Nat Med. 2007 Sep;13(9):1070-7
references: 17767167
references: Nat Rev Drug Discov. 2008 Dec;7(12):1001-12
references: 18989337