Therapeutics Targeting the Core Apoptotic Machinery

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Jun 2

PMID 34073507

Citations 8

Authors

Claudia Hamilton

Jennifer P Fox

Daniel B Longley

Catherine A Higgins

Affiliations

Soon will be listed here.

Abstract

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically "addicted" to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

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References

Algeciras-Schimnich A, Pietras E, Barnhart B, Legembre P, Vijayan S, Holbeck S . Two CD95 tumor classes with different sensitivities to antitumor drugs. Proc Natl Acad Sci U S A. 2003; 100(20):11445-50. PMC: 208777. DOI: 10.1073/pnas.2034995100. View

Ward G, Lewis E, Ahn J, Johnson C, Lyons J, Martins V . ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth. Mol Cancer Ther. 2018; 17(7):1381-1391. DOI: 10.1158/1535-7163.MCT-17-0848. View

Piggott L, Omidvar N, Marti Perez S, French R, Eberl M, Clarkson R . Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Res. 2011; 13(5):R88. PMC: 3262200. DOI: 10.1186/bcr2945. View

He Y, Koch R, Budamagunta V, Zhang P, Zhang X, Khan S . DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J Hematol Oncol. 2020; 13(1):95. PMC: 7364785. DOI: 10.1186/s13045-020-00928-9. View

Leverson J, Zhang H, Chen J, Tahir S, Phillips D, Xue J . Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015; 6:e1590. PMC: 4669759. DOI: 10.1038/cddis.2014.561. View

Sadahira K, Sagawa M, Nakazato T, Uchida H, Ikeda Y, Okamoto S . Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway. Int J Oncol. 2014; 45(6):2278-86. PMC: 4215583. DOI: 10.3892/ijo.2014.2652. View

Chai J, Du C, Wu J, Kyin S, Wang X, Shi Y . Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000; 406(6798):855-62. DOI: 10.1038/35022514. View

Peyre L, Meyer M, Hofman P, Roux J . TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms. Br J Cancer. 2020; 124(1):91-101. PMC: 7782794. DOI: 10.1038/s41416-020-01177-w. View

Herbst R, Eckhardt S, Kurzrock R, Ebbinghaus S, ODwyer P, Gordon M . Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol. 2010; 28(17):2839-46. DOI: 10.1200/JCO.2009.25.1991. View

10.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

11.

Yuan X, Gajan A, Chu Q, Xiong H, Wu K, Wu G . Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev. 2018; 37(4):733-748. PMC: 6138568. DOI: 10.1007/s10555-018-9728-y. View

12.

Graves J, Kordich J, Huang T, Piasecki J, Bush T, Sullivan T . Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity. Cancer Cell. 2014; 26(2):177-89. DOI: 10.1016/j.ccr.2014.04.028. View

13.

Hwang J, Kuruvilla J, Mendelson D, Pishvaian M, Deeken J, Siu L . Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010; 16(15):4038-45. PMC: 3703245. DOI: 10.1158/1078-0432.CCR-10-0822. View

14.

Yi H, Qiu M, Yuan L, Luo Q, Pan W, Zhou S . Bcl-2/Bcl-xl inhibitor APG-1252-M1 is a promising therapeutic strategy for gastric carcinoma. Cancer Med. 2020; 9(12):4197-4206. PMC: 7300393. DOI: 10.1002/cam4.3090. View

15.

Wang L, Doherty G, Judd A, Tao Z, Hansen T, Frey R . Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X Inhibitor. ACS Med Chem Lett. 2020; 11(10):1829-1836. PMC: 7549103. DOI: 10.1021/acsmedchemlett.9b00568. View

16.

Legler K, Hauser C, Egberts J, Willms A, Heneweer C, Boretius S . The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells. Cell Death Dis. 2018; 9(5):445. PMC: 5906476. DOI: 10.1038/s41419-018-0478-0. View

17.

Le Tourneau C, Tao Y, Gomez-Roca C, Cristina V, Borcoman E, Deutsch E . Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck. Clin Cancer Res. 2020; 26(24):6429-6436. DOI: 10.1158/1078-0432.CCR-20-0425. View

18.

Galligan L, Longley D, McEwan M, Wilson T, McLaughlin K, Johnston P . Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP. Mol Cancer Ther. 2005; 4(12):2026-36. DOI: 10.1158/1535-7163.MCT-05-0262. View

19.

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno A, Le Toumelin-Braizat G . The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016; 538(7626):477-482. DOI: 10.1038/nature19830. View

20.

Crawford N, Salvucci M, Hellwig C, Lincoln F, Mooney R, OConnor C . Simulating and predicting cellular and in vivo responses of colon cancer to combined treatment with chemotherapy and IAP antagonist Birinapant/TL32711. Cell Death Differ. 2018; 25(11):1952-1966. PMC: 5989936. DOI: 10.1038/s41418-018-0082-y. View