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Genentech and AbbVie are dedicated to researching BCL-2 and its role in apoptosis and cancer pathophysiology

Evasion of apoptosis in cancer tumor development

Damage to DNA can render a cell useless, or even harmful to an organism. Apoptosis, or programmed cell death, evolved as a rapid and irreversible process to efficiently eliminate dysfunctional cells.1

A hallmark of cancer is the ability of malignant cells to evade apoptosis.2 Cancer cells exhibit many characteristics that would readily trigger apoptosis in healthy cells—for example, they violate cell cycle checkpoints and can withstand exposure to cytotoxic agents.3 Because of these characteristics, cancer cells tend to survive. Apoptosis can be seen as an important barrier to developing cancer; avoiding apoptosis is integral to tumor development and resistance to therapy.3,4

The BCL-2 family of proteins and its role in apoptosis

The BCL-2 family of proteins is known as an important gatekeeper to the apoptotic response. This group of structurally related proteins comprises pro-apoptotic and anti-apoptotic members (Figure 2.1) that interact with one another.5

Short sequences of amino acids common to BCL-2 and other members of this protein family are known as BCL-2 homology (BH) motifs.5 At least 1 BH motif is contained in each of the BCL-2 family members. These motifs, in part, contribute to the function of each member.5,6

The BCL-2 family members can be classified into 3 functional groups: anti-apoptotic proteins such as BCL-2, pro-apoptotic effectors, and pro-apoptotic activators (Figure 2.1). Preclinical data suggest that activators, which contain only a single BH3 motif, are important mediators in the cellular response to stresses such as DNA damage.6

Effectors are those BCL-2 proteins closely associated with the mitochondrial membrane, and when stimulated by BH3-only activators, promote the formation of pores in the mitochondrial membrane, initiating the apoptotic program.7,8

Figure 2.1 The BCL-2 family5,6

BCL-2 family

Apoptosis-promoting effects from both effectors and activators are inhibited by direct interaction with anti-apoptotic BCL-2 family members.9 In preclinical models, BCL-2 binds and sequesters BH3-only activators and prevents them from interacting with the pore-forming effectors. Likewise, BCL-2 can directly influence effectors to prevent mitochondrial pore formation (Figure 2.2). The dynamic balance that occurs between anti-apoptotic members, such as BCL-2, and pro-apoptotic members helps determine whether the cell initiates apoptosis.6,7

Figure 2.2 Functional role of BCL-26,7

BCL-2 pathway of apoptosis inhibition

Tumor cells may become dependent on BCL-2 for survival

Similar to oncogene addiction, in which tumor cells rely on a single dominant gene for survival, tumor cells may also become dependent on BCL-2 in order to survive.5 In response to stress signals, malignant cells may express pro-apoptotic activators. Some cancer cells overexpress BCL-2,1 which can dampen this pro-apoptotic response. The result is in many cases an abundance of pro-apoptotic activators bound and sequestered by BCL-2. In this scenario, cancer cells are thought to be “primed” for apoptosis, in that they may contain sufficient amounts of the pro-apoptotic activators, if displaced from BCL-2, to induce programmed cell death (Figure 3.1). Cancers that depend on BCL-2 for survival in this way are likely to be sensitive to BCL-2 modulation.10

Figure 3.1 Cell priming10

Mitochondrion of primed tumor cell

BCL-2 expression in disease

The dynamic role of pro- and anti-apoptotic proteins, among other proteins, may alter the significance of increased BCL-2 expression in human disease. However, the wide variety of cancer types associated with aberrant expression of BCL-2 is consistent with its role as an apoptotic regulator (Table 3.2).10

BCL-2 expression in leukemia

Less than 5% of patients with chronic lymphocytic leukemia harbor a detectable BCL-2 gene rearrangement, although the vast majority overexpress BCL-2.11 Increased expression of BCL-2 is also found frequently in acute myeloid leukemia12 and in nearly all patients with acute lymphocytic leukemia.12

BCL-2 expression in non-Hodgkin lymphoma

In follicular lymphoma, an estimated 90% of patients harbor a t(14;18) chromosomal translocation in tumor cells,13,14 which is thought to cause overexpression of BCL-2 protein.15 More than 40% of diffuse large B-cell lymphoma patients were categorized as having relatively high BCL-2 expression.16

BCL-2 expression in solid tumors

BCL-2 may also play a role in nonhematologic tumors, and inappropriate expression has been observed in solid tumors such as prostate, breast, and small cell and non-small cell lung cancers.17-20 In small cell lung cancer, high BCL-2 expression in >90% of patients has been reported.19 Ovarian, neuroblastoma, bladder, colorectal, and some head and neck cancers have all exhibited significant levels of BCL-2 expression.21-25

Table 3.2 Select clinical evidence in cancer

Malignancy

BCL-2 expression

Chronic lymphocytic leukemia (CLL)

Relatively high level of BCL-2 expression documented in 95% of CLL cases compared to normal peripheral blood lymphocytes11

Acute myeloid leukemia (AML)

High expression of BCL-2 associated with poor response to chemotherapy26

Acute lymphocytic leukemia (ALL)

High levels of BCL-2 are found in nearly all patients with ALL12

Follicular lymphoma (FL)

BCL-2 overexpression is associated with chromosomal translocation in approximately 90% of follicular lymphomas.13,14

Diffuse large B-cell lymphoma (DLBCL)

Chromosomal translocations affecting BCL-2 occur in approximately 20% of DLBCL.27 BCL-2 expression is associated with poor overall survival within a specific subgroup of DLBCL28

Diverse solid tumors

Inappropriate expression of BCL-2 has been observed in solid tumors such as prostate, breast, and small cell and non-small cell lung cancers17-20

Cell priming

Cellular stresses endured by nearly all cancer cells—limited blood supply, reactive oxygen species, and exposure to chemotoxins—can lead to increases in pro-apoptotic proteins, much like they would in normal cells. When BCL-2 is overexpressed in cancer cells, it may inhibit the pro-apoptotic signals, allowing the cancer cell to survive under stressful conditions. The high levels of pro-apoptotic proteins bound and sequestered by increased BCL-2 may result in what is called a primed state (Figure 4.1). Primed cells are thought to have a high apoptotic potential: in other words, displacement of pro-apoptotic proteins from BCL-2 can result in a large enough increase in free pro-apoptotic proteins to initiate apoptosis.6

The primed state provides a strong rationale for conducting research related to the targeting and inhibition of BCL-2.

Ongoing BCL-2 research

Many anticancer approaches have shown to elicit their effects via apoptosis,3,29,30 in which BCL-2 might play a significant role. Some preclinical models suggested that inhibition of BCL-2 may potentiate the effect of conventional chemotoxic agents,31,32 warranting further study in a clinical setting. In preclinical models, overexpression of anti-apoptotic BCL-2 family members rendered cancer cells resistant to multiple classes of anticancer drugs, including DNA-damaging and antimicrotubule agents,33 nucleoside analogs,33 glucocorticoids,34 and immunotherapy.34 Further study of the role of BCL-2 in acquired resistance to cancer therapy is required to substantiate these results.

Figure 4.1 Cell priming10

Mitochondrion of primed tumor cell
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      Anagnostou VK, Lowery FJ, Zolota V, et al. High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology. BMC Cancer. 2010;10:186. PMID: 20459695

    • Henriksen R, Wilander E, Oberg K. Expression and prognostic significance of Bcl-2 in ovarian tumours. Br J Cancer. 1995;72:1324-1329. PMID: 7577491

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    • Lamers F, Schild L, den Hartog IJ, et al. Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer. 2012;48:3093-3103. PMID: 22366560

      Lamers F, Schild L, den Hartog IJ, et al. Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer. 2012;48:3093-3103. PMID: 22366560

    • Swellam M, Abd-Elmaksoud N, Halim MH, Khatab H, Khiry H. Incidence of Bcl-2 expression in bladder cancer: relation to schistosomiasis. Clin Biochem. 2004;37:798-802. PMID: 15329319

      Swellam M, Abd-Elmaksoud N, Halim MH, Khatab H, Khiry H. Incidence of Bcl-2 expression in bladder cancer: relation to schistosomiasis. Clin Biochem. 2004;37:798-802. PMID: 15329319

    • Zhao DP, Ding XW, Peng JP, Zheng YX, Zhang SZ. Prognostic significance of bcl-2 and p53 expression in colorectal carcinoma. J Zhejiang Univ Sci B. 2005;6:1163-1169. PMID:16358373

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      Iqbal J, Neppalli VT, Wright G, et al. BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:961-968. PMID: 16418494

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