TUMOR DEPENDENCY

Overview

The tumor dependency oncology research approach involves identifying and targeting mechanisms and dependencies that are unique to malignant tumors.1 This area of research and development has produced new targeted therapies which may address one or more of the biological hallmarks of cancer which tumors exploit to proliferate, such as resisting cell death (avoiding apoptosis), sustaining proliferative signaling, evading growth suppressors, enabling replicative immortality.1

The ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation (cell replication) but also by the rate of cell attrition (cell death):1

  • Apoptosis, or programmed cell death, represents a major source of cell attrition.1
    • Sensors (intrinsic or extrinsic) are responsible for monitoring the extracellular and intracellular environment for conditions of normality or abnormality that influence whether a cell should live or die; these sentinels include cell surface receptors that bind survival or death factors.1
    • Effectors (capsases) are regulated by the sensors and ultimately carry out the execution of the death program through selective destruction of subcellular structures and organelles and of the genome.1
    • The BCL-2 family of proteins in the intrinsic apoptosis pathway are "sensors" or "regulators" which control cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of cytochrome C, subsequent caspase ("effectors") activation, and the resulting apoptosis.2
    • The tumor necrosis factor (TNF) protein receptor superfamily in the extrinsic apoptosis pathway includes tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 (DR4 and DR5) that when bound to their ligands, induce the ultimate activation of the downstream caspases leading to apoptosis.3,12
  • DNA repair, for continued cell cycle progression and prevention of cell necrosis, is part of the cellular mechanisms that potentiate continuous cell replication.4
    • ADP ribosylation reactions are needed following DNA damage and for cells to progress through G2 and M phases of the cell cycle.4
    • The poly (ADP-ribose) polymerases (PARPs) are an emerging family of enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins (poly ADPribosylation). 4
    • PARP is involved in base excision repair (BER) in response to singlestranded DNA breaks (SSBs) and is a component of the BER complex, which consists of DNA ligase III, DNA polymerase beta, and the XRCC1 protein.4
  • Epigenetic regulation, including acetylation and other histone modifications, control essential transcriptional regulatory processes in the cell.5
    • The bromodomain and extraterminal (BET) family proteins associate with transcriptional activation through interaction with acetylated chromatin, therefore playing a key role as epigenetic regulators. 6
    • Bromodomains, which are proteins with acetyl-lysine binding modules, function as the principal mediators of molecular recognition of acetylated chromatin and therefore have a key role in transcriptional activation.6
    • Bromodomains of BET proteins bind to acetylated chromatin during interphase but also remain attached to chromosomes during mitosis.5
    • BET proteins play a prominent role in cell proliferation.5

Therapeutic Potential

  • Acquired resistance to apoptosis is a hallmark of most, if not all types of cancer.1
    • In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event.7
    • Dysregulation of the apoptotic pathways can not only promote tumorigenesis, but can also render cancer cells resistant to conventional anti-cancer agents, since chemotherapy- and radiotherapy-induced killing of cancer cells is mainly mediated through activation of apoptosis.8
  • Overexpression of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-1) disrupts the dynamic balance of anti- and pro-apoptotic proteins, which may promote cancer cell survival.8,9
    • The overexpression of these proteins is seen in a wide variety of hematologic malignancies and solid tumors.8,10
    • The heterogeneity among tumors, even of the same type, necessitates a continued effort to further investigate mechanisms of apoptosis dysregulation in distinct cancer cell types.8
  • Strategies to inhibit anti-apoptotic BCL-2 proteins include reducing protein expression by targeting the corresponding mRNA with an antisense oligonucleotide compound as well as blocking anti-apoptotic activity by targeting at the protein level.8,9
    • There is interest in developing drugs that mimic the action of the BH3 domain by binding to one or more of the BCL-2-like proteins and triggering the apoptotic program.9
  • TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumors, therefore, inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumor onset, progression, and treatment resisitance.11
    • TRAIL can bind as a trimer to any of four membrane-bound and one soluble receptor, but only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) with intracellular functional death domains (DDs) that can induce apoptosis of tumor cells.12
    • Studies have demonstrated that TRAIL-R1 and R2 receptor agonists (TRAs) are generally well tolerated and that TRAIL can selectively trigger apoptosis in tumor cells across a wide range of tumor types, including colorectal cancer, lung cancer, pancreatic cancer, acute myeloid leukemia and non-Hodgkin lymphoma, without affecting normal cells.11-15
  • Intracellular sensors monitor the cell’s well-being and activate the death pathway in response to detecting abnormalities, including DNA damage, signaling imbalance provoked by oncogene action, survival factor insufficiency, or hypoxia.1
    • Chemotherapies causing cytotoxic DNA damage and damage caused by radiation therapies may elicit relapse responses that signal the activation of oncogenes and increased production of repair enzymes that put tumor cells in "survival mode".1
    • The accumulation of DNA lesions has been found to result in a significant increase in PARP levels in cells. Evidence for an important role of PARP in DNA repair comes from the finding that DNA damaging agents and radiation-induced DNA damage causes increased PARP activity.3
    • By targeting and inhibiting these survival mechanisms, such as PARP, relapse after treatments can be fought directly in a way that tumor cells cannot overcome.3
    • PARP inhibitors may potentiate the effectiveness of chemotherapy or radiation therapy.16
    • Tumor cells that are deficient in one or more of the DNA repair mechanisms such as homologous recombination (synthetic lethality).17,18
    • Inhibition of PARP-1/2 is synthetically lethal with the loss of function of either the BRCA1 or BRCA2 tumor suppressor gene.18
  • BET family proteins are involved in promoting aberrant oncogene expression in a variety of cancers.19-22
    • Overexpression and gain-of-function mutations of BET proteins can alter gene transcription, histone modification, DNA repair, and apoptosis.23
    • BET proteins serve to regulate the expression of important oncogenes, including those involved in apoptosis as well as cell cycle progression.6
    • Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes.23,24
    • Genetic rearrangements of BRD-containing proteins have been linked to the development of a number of extremely aggressive tumors.25
    • Small molecule inhibition of BET proteins have been investigated and demonstrate promising activity in both solid and hematologic malignancies.6
  1. Hanahan D, et al. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. (Image)
  2. Kale J, et al. BCL-2 family proteins: changing partners in the dance towards death. Cell Death and Differentiation. 2018;25:65–80.
  3. Ghobrial IM, et al. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55(3):178-94.
  4. Morales JC, et al. Review of Poly (ADP-ribose) Polymerase (PARP) Mechanisms of Action and Rationale for Targeting in Cancer and Other Diseases. Crit Rev Eukaryot Gene Expr. 2014;24(1): 5–28.
  5. Garcia-Gutierrez P, Mundi M, Garcia-Dominguez M. Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B. J Cell Sci. 2012;125(Pt 15):3671-3680.
  6. Wadhwa E, Nicolaides T. Bromodomain inhibitor review: bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus. 2016;8(5):e620.
  7. Ashkenazi A, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16:273–284. (image)
  8. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
  9. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
  10. Agarwal B, et al. Bcl-2 family of proteins in indolent B-cell non-Hodgkin's lymphoma: study of 116 cases. Am J Hematol. 2002 Aug;70(4):278-82.
  11. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nature Reviews. 2008;8:782-798.
  12. Lemke J, von Karstedt S, Zinngrebe J, Walczak H. Getting TRAIL back on track for cancer therapy. Cell Death and Differentiation. 2014;21:1350-1364.
  13. von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 2017;17(6):352-366.
  14. Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer. 2017;117(8):1089-1098.
  15. Kretz AL, et al. TRAILBLAZING Strategies for Cancer Treatment. Cancers. 2019:11;456.
  16. Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13:6252-6256.
  17. Anders CK, Winer EP, Ford JM, et al. Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16:4702-4710.
  18. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther. 2015;353(3):446-457.
  19. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6(8):5501-5516.
  20. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
  21. Liu S, Walker SR, Nelson EA, et al. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol Cancer Ther. 2014;13(5):1194-1205.
  22. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669-16674.
  23. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16(4):241-263.
  24. Jung M, Gelato KA, Fernández-Montalván A, Siegel S, Haendler B. Targeting BET bromodomains for cancer treatment. Epigenomics. 2015;7(3):487-501.
  25. Muller S, Filippakopoulos P, Knapp S. Bromodomains as therapeutic targets. Expert Rev Mol Med. 2011;13:e29.

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