, Volume 23, Issue 2, pp 93–112 | Cite as

Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies

  • Ali Razaghi
  • Kirsten Heimann
  • Patrick M. Schaeffer
  • Spencer B. Gibson


Cancer is a primary cause of human fatality and conventional cancer therapies, e.g., chemotherapy, are often associated with adverse side-effects, tumor drug-resistance, and recurrence. Molecularly targeted therapy, composed of small-molecule inhibitors and immunotherapy (e.g., monoclonal antibody and cancer vaccines), is a less harmful alternative being more effective against cancer cells whilst preserving healthy tissues. Drug-resistance, however, caused by negative regulation of cell death signaling pathways, is still a challenge. Circumvention of negative regulators of cell death pathways or development of predictive and response biomarkers is, therefore, quintessential. This review critically discusses the current state of knowledge on targeting negative regulators of cell death signaling pathways including apoptosis, ferroptosis, necroptosis, autophagy, and anoikis and evaluates the recent advances in clinical and preclinical research on biomarkers of negative regulators. It aims to provide a comprehensive platform for designing efficacious polytherapies including novel agents for restoring cell death signaling pathways or targeting alternative resistance pathways to improve the chances for antitumor responses. Overall, it is concluded that nonapoptotic cell death pathways are a potential research arena for drug discovery, development of novel biomarkers and targeted therapies.


Cancer targeted therapy Drug resistance Cell death pathway Negative regulator Biomarker Immunotherapy 


Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10495_2018_1440_MOESM1_ESM.mp4 (7 mb)
Supplementary Video 1. Anti-apoptotic Bcl-xl protein negatively regulates Fas-mediated apoptosis. Subsequently, SMI deactivates Bcl-xl and unblocks the signal transduction pathway, restoring apoptosis. Bax, Bcl-2-associated X protein; BID, BH3 interacting-domain death agonist; Casp-8, caspase-8; CYT-C, cytochrome-c; FADD, Fas-associated protein with death domain; FasL, Fas ligand; RIP, receptor interacting protein; SMI, small-molecule inhibitor; tBID, truncated BID (MP4 7150 KB)


  1. 1.
    Biemar F, Foti M (2013) Global progress against cancer-challenges and opportunities. Cancer Biol Med 10:183–186.  https://doi.org/10.7497/j.issn.2095-3941.2013.04.001 PubMedPubMedCentralGoogle Scholar
  2. 2.
    Huang M, Shen A, Ding J, Geng M (2014) Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol Sci 35:41–50.  https://doi.org/10.1016/j.tips.2013.11.004 PubMedCrossRefGoogle Scholar
  3. 3.
    Lambert G, Estevez-Salmeron L, Oh S et al (2011) An analogy between the evolution of drug resistance in bacterial communities and malignant tissues. Nat Rev Cancer 11:375–382.  https://doi.org/10.1038/nrc3039 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Housman G, Byler S, Heerboth S et al (2014) Drug resistance in cancer: an overview. Cancers 6:1769–1792.  https://doi.org/10.3390/cancers6031769 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hata AN, Engelman JA, Faber AC (2015) The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov 5:475–487.  https://doi.org/10.1158/2159-8290.CD-15-0011 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674.  https://doi.org/10.1016/j.cell.2011.02.013 PubMedCrossRefGoogle Scholar
  7. 7.
    Garraway LA, Janne PA (2012) Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2:214–226.  https://doi.org/10.1158/2159-8290.CD-12-0012 PubMedCrossRefGoogle Scholar
  8. 8.
    Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87.  https://doi.org/10.1186/1756-9966-30-87 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kasibhatla S, Tseng B (2003) Why target apoptosis in cancer treatment? Mol Cancer Ther 2:573–580PubMedGoogle Scholar
  10. 10.
    Xie Y, Hou W, Song X et al (2016) Ferroptosis: process and function. Cell Death Differ 23:369–379.  https://doi.org/10.1038/cdd.2015.158 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Razaghi A, Owens L, Heimann K (2016) Review of the recombinant human interferon gamma as an immunotherapeutic: impacts of production platforms and glycosylation. J Biotechnol 240:48–60.  https://doi.org/10.1016/j.jbiotec.2016.10.022 PubMedCrossRefGoogle Scholar
  12. 12.
    Lee HJ, Kim JY, Park JE, Yoon YD, Tsang BK, Kim JM (2016) Induction of Fas-mediated apoptosis by interferon-gamma is dependent on granulosa cell differentiation and follicular maturation in the rat ovary. Dev Reprod 20:315–329.  https://doi.org/10.12717/DR.2016.20.4.315 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Razaghi A, Villacres C, Jung V et al (2017) Improved therapeutic efficacy of mammalian expressed-recombinant interferon gamma against ovarian cancer cells. Exp Cell Res 359:20–29.  https://doi.org/10.1016/j.yexcr.2017.08.014 PubMedCrossRefGoogle Scholar
  14. 14.
    Guicciardi ME, Gores GJ (2009) Life and death by death receptors. FASEB J 23:1625–1637.  https://doi.org/10.1096/fj.08-111005 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Iyer S, Bell F, Westphal D et al (2015) Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains. Cell Death Differ 22:1665–1675.  https://doi.org/10.1038/cdd.2015.15 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Pobezinskaya YL, Liu Z (2012) The role of TRADD in death receptor signaling. Cell Cycle 11:871–876.  https://doi.org/10.4161/cc.11.5.19300 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Allen JE, Kline CL, Prabhu VV et al (2016) Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget 7:74380–74392.  https://doi.org/10.18632/oncotarget.11814 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    von Karstedt S, Conti A, Nobis M et al (2015) Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell 27:561–573.  https://doi.org/10.1016/j.ccell.2015.02.014 CrossRefGoogle Scholar
  19. 19.
    Chen L, Park SM, Tumanov AV et al (2010) CD95 promotes tumour growth. Nature 465:492–496.  https://doi.org/10.1038/nature09075 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Hartwig T, Montinaro A, von Karstedt S et al (2017) The TRAIL-Induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol Cell 65:730–742 e735.  https://doi.org/10.1016/j.molcel.2017.01.021 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Shirley S, Micheau O (2013) Targeting c-FLIP in cancer. Cancer Lett 332:141–150.  https://doi.org/10.1016/j.canlet.2010.10.009 PubMedCrossRefGoogle Scholar
  22. 22.
    Fox JL, MacFarlane M (2016) Targeting cell death signalling in cancer: minimising ‘Collateral damage’. Br J Cancer 115:5–11.  https://doi.org/10.1038/bjc.2016.111 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Lemke J, von Karstedt S, Zinngrebe J, Walczak H (2014) Getting TRAIL back on track for cancer therapy. Cell Death Differ 21:1350–1364.  https://doi.org/10.1038/cdd.2014.81 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Lee EW, Seo J, Jeong M, Lee S, Song J (2012) The roles of FADD in extrinsic apoptosis and necroptosis. BMB Rep 45:496–508.  https://doi.org/10.5483/BMBRep.2012.45.9.186 PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang Y, Zhu J, Tang Y et al (2011) X-linked inhibitor of apoptosis positive nuclear labeling: a new independent prognostic biomarker of breast invasive ductal carcinoma. Diagn Pathol 6:49.  https://doi.org/10.1186/1746-1596-6-49 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Lafont E, Kantari-Mimoun C, Draber P et al (2017) The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death. EMBO J 36:1147–1166.  https://doi.org/10.15252/embj.201695699 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Probst BL, Liu L, Ramesh V et al (2010) Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-alpha-dependent manner. Cell Death Differ 17:1645–1654.  https://doi.org/10.1038/cdd.2010.44 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Vamos M, Welsh K, Finlay D et al (2013) Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP. ACS Chem Biol 8:725–732.  https://doi.org/10.1021/cb3005512 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Fenstermaker RA (2014) Survivin as a cancer vaccine target. J Vaccines Vaccin.  https://doi.org/10.4172/2157-7560.1000230 Google Scholar
  30. 30.
    Ausserlechner MJ, Hagenbuchner J (2016) Mitochondrial survivin—an Achilles’ heel in cancer chemoresistance. Mol Cell Oncol 3:e1076589.  https://doi.org/10.1080/23723556.2015.1076589 PubMedCrossRefGoogle Scholar
  31. 31.
    Pan R, Hogdal LJ, Benito JM et al (2014) Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 4:362–375.  https://doi.org/10.1158/2159-8290.CD-13-0609 PubMedCrossRefGoogle Scholar
  32. 32.
    Cang S, Iragavarapu C, Savooji J, Song Y, Liu D (2015) ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol 8:129.  https://doi.org/10.1186/s13045-015-0224-3 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Rudin CM, Hann CL, Garon EB et al (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18:3163–3169.  https://doi.org/10.1158/1078-0432.CCR-11-3090 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Del Poeta G, Postorino M, Pupo L et al (2016) Venetoclax: Bcl-2 inhibition for the treatment of chronic lymphocytic leukemia. Drugs Today 52:249–260.  https://doi.org/10.1358/dot.2016.52.4.2470954 PubMedGoogle Scholar
  35. 35.
    Inoue-Yamauchi A, Jeng PS, Kim K et al (2017) Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy. Nat Commun 8:16078.  https://doi.org/10.1038/ncomms16078 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Or CR, Chang Y, Lin WC et al. (2016) Obatoclax, a pan-BCL-2 inhibitor, targets cyclin D1 for degradation to induce antiproliferation in human colorectal carcinoma cells. Int J Mol Sci 18.  https://doi.org/10.3390/ijms18010044
  37. 37.
    Oki Y, Copeland A, Hagemeister F et al (2012) Experience with obatoclax mesylate (GX15–070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. Blood 119:2171–2172.  https://doi.org/10.1182/blood-2011-11-391037 PubMedCrossRefGoogle Scholar
  38. 38.
    Safa AR (2016) Resistance to cell death and its modulation in cancer stem cells. Crit Rev Oncog 21:203–219.  https://doi.org/10.1615/CritRevOncog.2016016976 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Burton TR, Eisenstat DD, Gibson SB (2009) BNIP3 (Bcl-2 19 kDa interacting protein) acts as transcriptional repressor of apoptosis-inducing factor expression preventing cell death in human malignant gliomas. J Neurosci 29:4189–4199.  https://doi.org/10.1523/JNEUROSCI.5747-08.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Li F, Zhang J, Arfuso F et al (2015) NF-κB in cancer therapy. Arch Toxicol 89:711–731.  https://doi.org/10.1007/s00204-015-1470-4 PubMedCrossRefGoogle Scholar
  41. 41.
    Godwin P, Baird AM, Heavey S, Barr MP, O’Byrne KJ, Gately K (2013) Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front Oncol 3:120.  https://doi.org/10.3389/fonc.2013.00120 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Douer D (2003) Arsenic trioxide (Trisenox(R)) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation. Oncologist 8:132–140.  https://doi.org/10.1634/theoncologist.8-2-132 PubMedCrossRefGoogle Scholar
  43. 43.
    Shono Y, Tuckett AZ, Liou HC et al (2016) Characterization of a c-Rel inhibitor that mediates anticancer properties in hematologic malignancies by blocking NF-kB-controlled oxidative stress responses. Cancer Res 76:377–389.  https://doi.org/10.1158/0008-5472.CAN-14-2814 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Fabre C, Mimura N, Bobb K et al (2012) Dual inhibition of canonical and noncanonical NF-kB pathways demonstrates significant antitumor activities in multiple myeloma. Clin Cancer Res 18:4669–4681.  https://doi.org/10.1158/1078-0432.CCR-12-0779 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Yamamoto M, Horie R, Takeiri M, Kozawa I, Umezawa K (2008) Inactivation of NF-kB components by covalent binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem 51:5780–5788.  https://doi.org/10.1021/jm8006245 PubMedCrossRefGoogle Scholar
  46. 46.
    Vaisitti T, Gaudino F, Ouk S et al (2017) Targeting metabolism and survival in chronic lymphocytic leukemia and Richter syndrome cells by a novel NF-kappaB inhibitor. Haematologica 102:1878–1889.  https://doi.org/10.3324/haematol.2017.173419 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Blakely CM, Pazarentzos E, Olivas V et al (2015) NF-kappaB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep 11:98–110.  https://doi.org/10.1016/j.celrep.2015.03.012 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Hughes MA, Powley IR, Jukes-Jones R et al (2016) Co-operative and hierarchical binding of c-FLIP and caspase-8: a unified model defines how c-FLIP isoforms differentially control cell fate. Mol Cell 61:834–849.  https://doi.org/10.1016/j.molcel.2016.02.023 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Longley DB, Wilson TR, McEwan M et al (2006) c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene 25:838–848.  https://doi.org/10.1038/sj.onc.1209122 PubMedCrossRefGoogle Scholar
  50. 50.
    Schinske KA, Nyati S, Khan AP et al (2011) A novel kinase inhibitor of FADD phosphorylation chemosensitizes through the inhibition of NF-kappaB. Mol Cancer Ther 10:1807–1817.  https://doi.org/10.1158/1535-7163.MCT-11-0362 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Ramos-Miguel A, Garcia-Fuster MJ, Callado LF, La Harpe R, Meana JJ, Garcia-Sevilla JA (2009) Phosphorylation of FADD (Fas-associated death domain protein) at serine 194 is increased in the prefrontal cortex of opiate abusers: relation to mitogen activated protein kinase, phosphoprotein enriched in astrocytes of 15 kDa, and Akt signaling pathways involved in neuroplasticity. Neuroscience 161:23–38.  https://doi.org/10.1016/j.neuroscience.2009.03.028 PubMedCrossRefGoogle Scholar
  52. 52.
    Nitulescu GM, Margina D, Juzenas P et al (2016) Akt inhibitors in cancer treatment: the long journey from drug discovery to clinical use (review). Int J Oncol 48:869–885.  https://doi.org/10.3892/ijo.2015.3306 PubMedCrossRefGoogle Scholar
  53. 53.
    Yap TA, Yan L, Patnaik A et al (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29:4688–4695.  https://doi.org/10.1200/JCO.2011.35.5263 PubMedCrossRefGoogle Scholar
  54. 54.
    Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464.  https://doi.org/10.1038/sj.onc.1209085 PubMedCrossRefGoogle Scholar
  55. 55.
    Oki Y, Fanale M, Romaguera J et al (2015) Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma. Br J Haematol 171:463–470.  https://doi.org/10.1111/bjh.13603 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ghobrial IM, Roccaro A, Hong F et al (2010) Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom’s macroglobulinemia. Clin Cancer Res 16:1033–1041.  https://doi.org/10.1158/1078-0432.CCR-09-1837 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Pal SK, Reckamp K, Yu H, Figlin RA (2010) Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 19:1355–1366.  https://doi.org/10.1517/13543784.2010.520701 PubMedCrossRefGoogle Scholar
  58. 58.
    Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64.  https://doi.org/10.3389/fonc.2014.00064 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Henson E, Chen Y, Gibson S (2017) EGFR family members’ regulation of autophagy is at a crossroads of cell survival and death in cancer. Cancers.  https://doi.org/10.3390/cancers9040027 PubMedPubMedCentralGoogle Scholar
  60. 60.
    Wei Y, Zou Z, Becker N et al (2013) EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154:1269–1284.  https://doi.org/10.1016/j.cell.2013.08.015 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Ying WZ, Zhang HG, Sanders PW (2007) EGF receptor activity modulates apoptosis induced by inhibition of the proteasome of vascular smooth muscle cells. J Am Soc Nephrol 18:131–142.  https://doi.org/10.1681/ASN.2006040333 PubMedCrossRefGoogle Scholar
  62. 62.
    Patrick A, Blevins M, Krueger A et al (2014) Abstract B102: targeting the SIX1/EYA transcriptional complex as a potential anti-cancer therapy. Mol Cancer Ther 12:B102-B102.  https://doi.org/10.1158/1535-7163.targ-13-b102 Google Scholar
  63. 63.
    Wang H, Li X, Liu H et al (2016) Six1 induces protein synthesis signaling expression in duck myoblasts mainly via up-regulation of mTOR. Genet Mol Biol 39:151–161.  https://doi.org/10.1590/1678-4685-GMB-2015-0075 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Armat M, Bakhshaiesh TO, Sabzichi M et al (2016) The role of Six1 signaling in paclitaxel-dependent apoptosis in MCF-7 cell line. Bosn J Basic Med Sci 16:28–34.  https://doi.org/10.17305/bjbms.2016.674 PubMedPubMedCentralGoogle Scholar
  65. 65.
    Blevins MA, Towers CG, Patrick AN, Zhao R, Ford HL (2015) The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 19:213–225.  https://doi.org/10.1517/14728222.2014.978860 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Zeng J, Liu D, Qiu Z et al (2014) GSK3beta overexpression indicates poor prognosis and its inhibition reduces cell proliferation and survival of non-small cell lung cancer cells. PLoS ONE 9:e91231.  https://doi.org/10.1371/journal.pone.0091231 PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072.  https://doi.org/10.1016/j.cell.2012.03.042 PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Jego G, Hazoume A, Seigneuric R, Garrido C (2013) Targeting heat shock proteins in cancer. Cancer Lett 332:275–285.  https://doi.org/10.1016/j.canlet.2010.10.014 PubMedCrossRefGoogle Scholar
  69. 69.
    Chatterjee S, Burns TF. (2017) Targeting heat shock proteins in cancer: a promising therapeutic approach. Int J Mol Sci 18.  https://doi.org/10.3390/ijms18091978
  70. 70.
    Sakamoto H, Mashima T, Yamamoto K, Tsuruo T (2002) Modulation of heat-shock protein 27 (Hsp27) anti-apoptotic activity by methylglyoxal modification. J Biol Chem 277:45770–45775.  https://doi.org/10.1074/jbc.M207485200 PubMedCrossRefGoogle Scholar
  71. 71.
    Oba M, Yano S, Shuto T, Suico M, Eguma A, Kai H (2008) IFN-γ down-regulates Hsp27 and enhances hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo. Int J Oncol.  https://doi.org/10.3892/ijo.32.6.1317 PubMedGoogle Scholar
  72. 72.
    Paoli P, Giannoni E, Chiarugi P (2013) Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 1833:3481–3498.  https://doi.org/10.1016/j.bbamcr.2013.06.026 PubMedCrossRefGoogle Scholar
  73. 73.
    Su Z, Yang Z, Xie L, DeWitt JP, Chen Y (2016) Cancer therapy in the necroptosis era. Cell Death Differ 23:748–756.  https://doi.org/10.1038/cdd.2016.8 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Lalaoui N, Brumatti G (2017) Relevance of necroptosis in cancer. Immunol Cell Biol 95:137–145.  https://doi.org/10.1038/icb.2016.120 PubMedCrossRefGoogle Scholar
  75. 75.
    Seo J, Lee E-W, Song J (2016) New role of E3 ubiquitin ligase in the regulation of necroptosis. BMB Reports 49:247–248.  https://doi.org/10.5483/BMBRep.2016.49.5.067 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Seo J, Lee E-W, Sung H et al (2016) CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3. Nat Cell Biol 18:291–302.  https://doi.org/10.1038/ncb3314 PubMedCrossRefGoogle Scholar
  77. 77.
    Osborn SL, Diehl G, Han SJ et al (2010) Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis. Proc Natl Acad Sci USA 107:13034–13039.  https://doi.org/10.1073/pnas.1005997107 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Yang YP, Hu LF, Zheng HF et al (2013) Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol Sin 34:625–635.  https://doi.org/10.1038/aps.2013.5 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Polivka J Jr, Janku F (2014) Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 142:164–175.  https://doi.org/10.1016/j.pharmthera.2013.12.004 PubMedCrossRefGoogle Scholar
  80. 80.
    Liang C (2010) Negative regulation of autophagy. Cell Death Differ 17:1807–1815.  https://doi.org/10.1038/cdd.2010.115 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Atkins MB, Yasothan U, Kirkpatrick P (2009) Everolimus. Nat Rev Drug Discov 8:535–536.  https://doi.org/10.1038/nrd2924 PubMedCrossRefGoogle Scholar
  82. 82.
    Popovics P, Frigo DE, Schally AV, Rick FG (2015) Targeting the 5′-AMP-activated protein kinase and related metabolic pathways for the treatment of prostate cancer. Expert Opin Ther Targets 19:617–632.  https://doi.org/10.1517/14728222.2015.1005603 PubMedCrossRefGoogle Scholar
  83. 83.
    Rehman G, Shehzad A, Khan AL, Hamayun M (2014) Role of AMP-activated protein kinase in cancer therapy. Arch Pharm 347:457–468.  https://doi.org/10.1002/ardp.201300402 CrossRefGoogle Scholar
  84. 84.
    Faubert B, Boily G, Izreig S et al (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17:113–124.  https://doi.org/10.1016/j.cmet.2012.12.001 PubMedCrossRefGoogle Scholar
  85. 85.
    Melosky B (2014) Review of EGFR TKIs in metastatic NSCLC, including ongoing trials. Front Oncol 4:244.  https://doi.org/10.3389/fonc.2014.00244 PubMedPubMedCentralGoogle Scholar
  86. 86.
    Yang WS, SriRamaratnam R, Welsch ME et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331.  https://doi.org/10.1016/j.cell.2013.12.010 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Dixon SJ, Stockwell BR (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10:9–17.  https://doi.org/10.1038/nchembio.1416 PubMedCrossRefGoogle Scholar
  88. 88.
    Ma S, Henson ES, Chen Y, Gibson SB (2016) Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis 7:e2307.  https://doi.org/10.1038/cddis.2016.208 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Drakes ML, Stiff PJ (2014) Harnessing immunosurveillance: current developments and future directions in cancer immunotherapy. Immunotargets Ther 3:151–165.  https://doi.org/10.2147/ITT.S37790 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Weiner LM, Murray JC, Shuptrine CW (2012) Antibody-based immunotherapy of cancer. Cell 148:1081–1084.  https://doi.org/10.1016/j.cell.2012.02.034 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY (2013) Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res 119:421–475.  https://doi.org/10.1016/B978-0-12-407190-2.00007-1 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Wilken JA, Webster KT, Maihle NJ (2010) Trastuzumab sensitizes ovarian cancer cells to EGFR-targeted therapeutics. J Ovarian Res 3:7.  https://doi.org/10.1186/1757-2215-3-7 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sotelo MJ, Garcia-Paredes B, Aguado C, Sastre J, Diaz-Rubio E (2014) Role of cetuximab in first-line treatment of metastatic colorectal cancer. World J Gastroenterol 20:4208–4219.  https://doi.org/10.3748/wjg.v20.i15.4208 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12:278–287.  https://doi.org/10.1038/nrc3236 PubMedCrossRefGoogle Scholar
  95. 95.
    Patel SB, Gill D, Garrido-Laguna I (2016) Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer. Onco Targets Ther 9:75–86.  https://doi.org/10.2147/OTT.S68558 PubMedCrossRefGoogle Scholar
  96. 96.
    Garnock-Jones KP, Keating GM, Scott LJ (2010) Trastuzumab: a review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Drugs 70:215–239.  https://doi.org/10.2165/11203700-000000000-00000 PubMedCrossRefGoogle Scholar
  97. 97.
    Rodriguez PC, Popa X, Martinez O et al (2016) A phase III clinical trial of the epidermal growth factor vaccine CIMAvax-EGF as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res 22:3782–3790.  https://doi.org/10.1158/1078-0432.CCR-15-0855 PubMedCrossRefGoogle Scholar
  98. 98.
    Saavedra D, Crombet T (2017) CIMAvax-EGF: a new therapeutic vaccine for advanced non-small cell lung cancer patients. Front Immunol 8:269.  https://doi.org/10.3389/fimmu.2017.00269 PubMedPubMedCentralGoogle Scholar
  99. 99.
    Hirschowitz EA, Foody T, Hidalgo GE, Yannelli JR (2007) Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer 57:365–372.  https://doi.org/10.1016/j.lungcan.2007.04.002 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Tanaka T, Kitamura H, Inoue R et al. (2013) Potential survival benefit of anti-apoptosis protein: survivin-derived peptide vaccine with and without interferon alpha therapy for patients with advanced or recurrent urothelial cancer—results from phase I clinical trials. Clin Dev Immunol 2013:262967.  https://doi.org/10.1155/2013/262967 PubMedPubMedCentralGoogle Scholar
  101. 101.
    Fenstermaker RA, Ciesielski MJ, Qiu J et al (2016) Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer Immunol Immunother 65:1339–1352.  https://doi.org/10.1007/s00262-016-1890-x PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Li R, Qian J, Zhang W et al (2014) Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma. Br J Haematol 166:690–701.  https://doi.org/10.1111/bjh.12943 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Bloch O, Crane CA, Fuks Y et al (2014) Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol 16:274–279.  https://doi.org/10.1093/neuonc/not203 PubMedCrossRefGoogle Scholar
  104. 104.
    Henry NL, Hayes DF (2012) Cancer biomarkers. Mol Oncol 6:140–146.  https://doi.org/10.1016/j.molonc.2012.01.010 PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ward TH, Cummings J, Dean E et al (2008) Biomarkers of apoptosis. Br J Cancer 99:841–846.  https://doi.org/10.1038/sj.bjc.6604519 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Krysan K, Dalwadi H, Sharma S, Pold M, Dubinett S (2004) Cyclooxygenase 2-dependent expression of survivin is critical for apoptosis resistance in non-small cell lung cancer. Cancer Res 64:6359–6362.  https://doi.org/10.1158/0008-5472.CAN-04-1681 PubMedCrossRefGoogle Scholar
  107. 107.
    Olsen D, Jorgensen JT (2014) Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects. Front Oncol 4:105.  https://doi.org/10.3389/fonc.2014.00105 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Punnoose EA, Leverson JD, Peale F et al (2016) Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist Venetoclax in multiple myeloma models. Mol Cancer Ther 15:1132–1144.  https://doi.org/10.1158/1535-7163.MCT-15-0730 PubMedCrossRefGoogle Scholar
  109. 109.
    Khalil AA, Kabapy NF, Deraz SF, Smith C (2011) Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta 1816:89–104.  https://doi.org/10.1016/j.bbcan.2011.05.001 PubMedGoogle Scholar
  110. 110.
    Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86.  https://doi.org/10.1379/CSC-99r.1 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Del Gaizo Moore V, Letai A (2013) BH3 profiling—measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett 332:202–205.  https://doi.org/10.1016/j.canlet.2011.12.021 PubMedCrossRefGoogle Scholar
  112. 112.
    Callagy GM, Pharoah PD, Pinder SE et al (2006) Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham Prognostic Index. Clin Cancer Res 12:2468–2475.  https://doi.org/10.1158/1078-0432.CCR-05-2719 PubMedCrossRefGoogle Scholar
  113. 113.
    Yoshino T, Shiina H, Urakami S et al (2006) Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res 12:6116–6124.  https://doi.org/10.1158/1078-0432.CCR-06-0147 PubMedCrossRefGoogle Scholar
  114. 114.
    Jaiswal PK, Goel A, Mittal RD (2015) Survivin: a molecular biomarker in cancer. Indian J Med Res 141:389–397.  https://doi.org/10.4103/0971-5916.159250 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Seligson DB, Hongo F, Huerta-Yepez S et al (2007) Expression of X-linked inhibitor of apoptosis protein is a strong predictor of human prostate cancer recurrence. Clin Cancer Res 13:6056–6063.  https://doi.org/10.1158/1078-0432.CCR-07-0960 PubMedCrossRefGoogle Scholar
  116. 116.
    Dutton A, Young LS, Murray PG (2006) The role of cellular FLICE inhibitory protein (c-FLIP) in the pathogenesis and treatment of cancer. Expert Opin Ther Targets 10:27–35.  https://doi.org/10.1517/14728222.10.1.27 PubMedCrossRefGoogle Scholar
  117. 117.
    Korkolopoulou P, Saetta AA, Levidou G et al (2007) c-FLIP expression in colorectal carcinomas: association with Fas/FasL expression and prognostic implications. Histopathology 51:150–156.  https://doi.org/10.1111/j.1365-2559.2007.02723.x PubMedCrossRefGoogle Scholar
  118. 118.
    Schrijvers ML, Pattje WJ, Slagter-Menkema L et al (2012) FADD expression as a prognosticator in early-stage glottic squamous cell carcinoma of the larynx treated primarily with radiotherapy. Int J Radiat Oncol Biol Phys 83:1220–1226.  https://doi.org/10.1016/j.ijrobp.2011.09.060 PubMedCrossRefGoogle Scholar
  119. 119.
    Kurozumi S, Yamaguchi Y, Hayashi S et al (2016) Prognostic value of the ubiquitin ligase carboxyl terminus of the Hsc70-interacting protein in postmenopausal breast cancer. Cancer Med 5:1873–1882.  https://doi.org/10.1002/cam4.780 PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Liang ZL, Kim M, Huang SM, Lee HJ, Kim JM (2013) Expression of carboxyl terminus of Hsp70-interacting protein (CHIP) indicates poor prognosis in human gallbladder carcinoma. Oncol Lett 5:813–818.  https://doi.org/10.3892/ol.2013.1138 PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Owonikoko TK, Khuri FR (2013) Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation. Am Soc Clin Oncol Educ Book.  https://doi.org/10.1200/EdBook_AM.2013.33.e395 PubMedPubMedCentralGoogle Scholar
  122. 122.
    Zeng J, Shi R, Cai CX et al (2015) Increased expression of Six1 correlates with progression and prognosis of prostate cancer. Cancer Cell Int 15:63.  https://doi.org/10.1186/s12935-015-0215-z PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Guerriero E, Capone F, Accardo M et al (2015) GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues. Eur J Histochem 59:2540.  https://doi.org/10.4081/ejh.2015.2540 PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Larrea E, Sole C, Manterola L et al. (2016) New concepts in cancer biomarkers: circulating miRNAs in liquid biopsies. Int J Mol Sci 17.  https://doi.org/10.3390/ijms17050627
  125. 125.
    Diaz LA Jr, Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 32:579–586.  https://doi.org/10.1200/JCO.2012.45.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Oellerich M, Schutz E, Beck J et al (2017) Using circulating cell-free DNA to monitor personalized cancer therapy. Crit Rev Clin Lab Sci 54:205–218.  https://doi.org/10.1080/10408363.2017.1299683 PubMedCrossRefGoogle Scholar
  127. 127.
    Vincent MD, Kuruvilla MS, Leighl NB, Kamel-Reid S (2012) Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol 19:S33–S44.  https://doi.org/10.3747/co.19.1149 PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Page K, Hava N, Ward B et al (2011) Detection of HER2 amplification in circulating free DNA in patients with breast cancer. Br J Cancer 104:1342–1348.  https://doi.org/10.1038/bjc.2011.89 PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Morin I, Dixon NE, Schaeffer PM (2010) Ultrasensitive detection of antibodies using a new Tus-Ter-lock immunoPCR system. Mol Biosyst 6:1173–1175.  https://doi.org/10.1039/c002163f PubMedCrossRefGoogle Scholar
  130. 130.
    Chang L, Li J, Wang L (2016) Immuno-PCR: an ultrasensitive immunoassay for biomolecular detection. Anal Chim Acta 910:12–24.  https://doi.org/10.1016/j.aca.2015.12.039 PubMedCrossRefGoogle Scholar
  131. 131.
    Li K, Wu D, Chen X et al (2014) Current and emerging biomarkers of cell death in human disease. Biomed Res Int 2014:690103.  https://doi.org/10.1155/2014/690103 PubMedPubMedCentralGoogle Scholar
  132. 132.
    Weigum SE, Floriano PN, Redding SW et al (2010) Nano-bio-chip sensor platform for examination of oral exfoliative cytology. Cancer Prev Res 3:518–528.  https://doi.org/10.1158/1940-6207.CAPR-09-0139 CrossRefGoogle Scholar
  133. 133.
    Morin I, Askin SP, Schaeffer PM (2011) IgG-detection devices for the Tus-Ter-lock immuno-PCR diagnostic platform. Analyst 136:4815–4821.  https://doi.org/10.1039/c1an15731k PubMedCrossRefGoogle Scholar
  134. 134.
    Dahdah DB, Morin I, Moreau MJ, Dixon NE, Schaeffer PM. (2009) Site-specific covalent attachment of DNA to proteins using a photoactivatable Tus-Ter complex. Chem Commun (Camb):3050–3052.  https://doi.org/10.1039/b900905a
  135. 135.
    Spencer KR, Wang J, Silk AW, Ganesan S, Kaufman HL, Mehnert JM (2016) Biomarkers for Immunotherapy: current developments and challenges. Am Soc Clin Oncol Educ Book 35:e493–e503.  https://doi.org/10.14694/EDBK_160766 PubMedCrossRefGoogle Scholar
  136. 136.
    Qiu H, Fang X, Luo Q, Ouyang G (2015) Cancer stem cells: a potential target for cancer therapy. Cell Mol Life Sci 72:3411–3424.  https://doi.org/10.1007/s00018-015-1920-4 PubMedCrossRefGoogle Scholar
  137. 137.
    Signore M, Ricci-Vitiani L, De Maria R (2013) Targeting apoptosis pathways in cancer stem cells. Cancer Lett 332:374–382.  https://doi.org/10.1016/j.canlet.2011.01.013 PubMedCrossRefGoogle Scholar
  138. 138.
    Giampazolias E, Zunino B, Dhayade S et al (2017) Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol 19:1116–1129.  https://doi.org/10.1038/ncb3596 PubMedCrossRefGoogle Scholar
  139. 139.
    Hannes S, Abhari BA, Fulda S (2016) Smac mimetic triggers necroptosis in pancreatic carcinoma cells when caspase activation is blocked. Cancer Lett 380:31–38.  https://doi.org/10.1016/j.canlet.2016.05.036 PubMedCrossRefGoogle Scholar
  140. 140.
    Lopez JS, Banerji U (2017) Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol 14:57–66.  https://doi.org/10.1038/nrclinonc.2016.96 PubMedCrossRefGoogle Scholar
  141. 141.
    Ricci MS, Zong WX (2006) Chemotherapeutic approaches for targeting cell death pathways. Oncologist 11:342–357.  https://doi.org/10.1634/theoncologist.11-4-342 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Grazia G, Penna I, Perotti V, Anichini A, Tassi E (2014) Towards combinatorial targeted therapy in melanoma: from pre-clinical evidence to clinical application (review). Int J Oncol 45:929–949.  https://doi.org/10.3892/ijo.2014.2491 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ali Razaghi
    • 1
  • Kirsten Heimann
    • 1
  • Patrick M. Schaeffer
    • 1
  • Spencer B. Gibson
    • 2
    • 3
  1. 1.Centre for Biodiscovery and Molecular Development of TherapeuticsJames Cook UniversityTownsvilleAustralia
  2. 2.Research Institute in Oncology and HematologyCancerCare ManitobaWinnipegCanada
  3. 3.Departments of Biochemistry and Medical Genetics and ImmunologyUniversity of ManitobaWinnipegCanada

Personalised recommendations