Mimicking the BH3 domain to kill cancer cells

Chonghaile, Tríona Ní; Letaï, Anthony

doi:10.1038/onc.2009.52

Cited by 236 publications

(228 citation statements)

References 86 publications

(132 reference statements)

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“…42 However, the high basal levels of Bim-EL that we detect in IBC cells suggest an inherent vulnerability that could be exploited chemotherapeutically. Recent studies suggest that this approach may be broadly effective in both IBC and non-IBC cells that have high basal levels of Bim-EL, as the effectiveness of targeting cancer cells with kinase inhibitors has been shown to strongly correlate with Bim-EL expression.…”

Section: Discussionmentioning

confidence: 77%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

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Section: Discussionmentioning

confidence: 77%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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“…8 One of these compounds is ABT-737, which occasionally presents in vitro monotherapy toxicity. 5 It potently inhibits the BH3-binding activity of Bcl-2, Bcl-xL and Bcl-w but not that of Mcl-1 and Bfl-1. 9 ABT-737 promotes cell death by displacing, from its targets, 'BH3 activators' such as Bim or Puma (BH3-only proteins that can directly activate multi-domain proteins when free from anti-apoptotic proteins) 10,11 and/or active Bax.…”

mentioning

confidence: 95%

“…Small molecules that bind to the BH3-binding grove of Bcl-2 homologs (the so-called 'BH3 mimetics') have been developed as pro-apoptotic inhibitors of these proteins. 5 There are subtle yet significant differences in the BH3-binding interfaces of Bcl-2 homologs: Bim or Puma interact with all known Bcl-2 homologs, whereas Bad interacts preferentially with Bcl-2 and Bcl-xL and Noxa with Mcl-1. 6,7 These differences explain why currently known BH3-mimetics only inhibit subsets of anti-apoptotic proteins.…”

mentioning

confidence: 99%

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

et al. 2013

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Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa.

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“…Activators directly activate BAX and BAK. Activators and sensitizers antagonize antiapoptotic family members releasing BAX and BAK for activation (17)(18)(19)(20). The BH3 mimetic ABT-737 (developed by AbbVie) binds BCL-2 and BCL-x L (with poor affinity for MCL-1) to block BCL-2 family member interactions.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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Mimicking the BH3 domain to kill cancer cells

Cited by 236 publications

References 86 publications

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

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