Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4-and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1-and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.Apoptosis is one of the death phenotypes that can be triggered in tumor cells by anticancer agents. Resistance of tumor cells to apoptosis can account for treatment failure (18). One of the stimuli that can induce tumor cell death by apoptosis is the member of the tumor necrosis factor superfamily known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) (16). TRAIL has gained considerable interest in oncology since it displays specific antitumoral activity against a wide range of tumor cells (14, 41, 47) without significant side effects, at least in mice and monkeys (3,21,22).TRAIL triggers apoptosis upon engagement of one of its two agonistic receptors, named DR4 (death receptor 4) (33) and DR5 (death receptor 5) (7,46). In response to TRAIL, these receptors recruit the adaptor protein FADD (Fas-associated death domain), through death domain homophilic interactions (5), and the initiators procaspase-8 and -10, through death effector domain interactions with FADD, hence forming the macromolecular complex called DISC (death-inducing signaling complex). Within this complex, procaspase-8 and -10 are activated by autoproteolytic cleavage and initiate the caspase cascade leading to apoptosis (42).

The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.

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The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-x L , and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-x L predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-x L or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-x L /Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies. (Blood. 2012;119(24):5807-5816) IntroductionDefects in the mitochondrial apoptotic pathway regulated by the Bcl-2 family of proteins play a major role in cancer development and in conferring chemoresistance. 1 Within the family, Bax and Bak are essential for mitochondrial membrane permeabilization and cell death. 2 Prosurvival proteins (Bcl-2, Bcl-x L , Bcl-w, Mcl-1, A1) oppose Bax and Bak and ensure mitochondrial integrity and cell survival. 1 These prosurvival proteins also interact with distant relatives that share only 1 Bcl-2 Homology region, BH3, that is critical for their proapoptotic function. The BH3-only proteins such as Bim, Bad, Puma, and Noxa act as stress sensors and relieve the inhibition of Bax and Bak by the prosurvival proteins.The clinical efficacy of most anticancer therapeutics primarily reflects their ability to induce apoptosis. Resistance to conventional anticancer therapeutics (eg, etoposide) is often because of a failure to activate BH3-only proteins, for example because of mutation of the tumor suppressor p53, which is critical for transcriptional induction of Puma and Noxa after DNA damage. 3 Overexpression of prosurvival Bcl-2 proteins, or silencing of BH3-only protein expression, are also associated with inferior therapeutic outcomes. 4,5 BH3-mimetic drugs, such as ABT-737, were developed to directly counter such apoptotic blocks. ABT-737 binds avidly to Bcl-2, Bcl-x L , and Bcl-w, but not Mcl-1 or A1. 6,7 In preclinical studies, it demonstrated single agent efficacy against tumors with low Mcl-1 or A1 levels, such as follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and small cell lung carcinoma (SCLC). ABT-737 shows limited toxicity toward normal cells, although there is transient reduction of platelets and lymphocytes. 6,8 , an orally bioavailable compound in the same class with similar target specificity, also exhibited efficacy in various cancer-derived cell lines both in vitro and in vivo, 6,9,10 and is undergoing p...

The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.

Since its identification in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling cancer cells escape from TRAIL-induced cell death, will be required to optimally use the cytokine in clinics. The present review focuses on recent advances in the understanding of TRAIL signal transduction and discusses the existing and future challenges of TRAIL-based cancer therapy development.

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.