MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

Xiao, Yu; Nimmer, Paul; Sheppard, George S.; Bruncko, Milan; Hessler, Paul; Lü, Xin; Roberts-Rapp, Lisa; Pappano, William N.; Elmore, Steven W.; Souers, Andrew J.; Leverson, Joel D.; Phillips, Darren C.

doi:10.1158/1535-7163.mct-14-0928

Cited by 108 publications

(130 citation statements)

References 46 publications

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“…In breast cancers, overexpression of MCL-1 is associated with a poor prognosis2, consistent with the dependency of breast cancer cells, including those of the TNBC subtype, on MCL-1 for survival349. Nonetheless, few insights have been available regarding the mechanisms responsible for MCL-1 overexpression in breast cancer.…”

Section: Discussionmentioning

confidence: 88%

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors

Hiraki

Suzuki

Alam

et al. 2016

Sci Rep

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Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK → ERK and PI3K → AKT pathways, and in turn destabilizes MCL-1. The small molecules ABT-737 and ABT-263 target BCL-2, BCL-XL and BCL-w, but not MCL-1. We show that treatment with ABT-737 increases reactive oxygen species and thereby MUC1-C expression. In this way, MUC1-C is upregulated in TNBC cells resistant to ABT-737 or ABT-263. We also demonstrate that MUC1-C is necessary for the resistance-associated increases in MCL-1 levels. Significantly, combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and drug resistant TNBC cells. These findings indicate that targeting MUC1-C is a potential strategy for reversing MCL-1-mediated resistance in TNBC.

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Section: Discussionmentioning

confidence: 88%

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors

Hiraki

Suzuki

Alam

et al. 2016

Sci Rep

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“…The efficacy of the combination of ABT-263 and A-1210477 has been tested before in non-melanoma cancers 31,69 ; however, the mechanism of combination-induced cell death has not been analyzed. We utilized multiple approaches to investigate the contribution of NOXA and BIM, including the CRISPR/Cas9, shRNA techniques, as well as a NOXA-null line.…”

Section: Discussionmentioning

confidence: 99%

BH3 mimetics induce apoptosis independent of DRP-1 in melanoma

et al. 2018

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Despite the recent advancement in treating melanoma, options are still limited for patients without BRAF mutations or in relapse from current treatments. BH3 mimetics against members of the BCL-2 family have gained excitement with the recent success in hematological malignancies. However, single drug BH3 mimetic therapy in melanoma has limited effectiveness due to escape by the anti-apoptotic protein MCL-1 and/or survival of melanoma-initiating cells (MICs). We tested the efficacy of the BH3 mimetic combination of A-1210477 (an MCL-1 inhibitor) and ABT-263 (a BCL-2/BCL-XL/BCL-W inhibitor) in killing melanoma, especially MICs. We also sought to better define Dynamin-Related Protein 1 (DRP-1)’s role in melanoma; DRP-1 is known to interact with members of the BCL-2 family and is a possible therapeutic target for melanoma treatment. We used multiple assays (cell viability, apoptosis, bright field, immunoblot, and sphere formation), as well as the CRISPR/Cas9 genome-editing techniques. For clinical relevance, we employed patient samples of different mutation status, including some relapsed from current treatments such as anti-PD-1 immunotherapy. We found the BH3 mimetic combination kill both the MICs and non-MICs (bulk of melanoma) in all cell lines and patient samples irrespective of the mutation status or relapsed state (p < 0.05). Unexpectedly, the major pro-apoptotic proteins, NOXA and BIM, are not necessary for the combination-induced cell death. Furthermore, the combination impedes the activation of DRP-1, and inhibition of DRP-1 further enhances apoptosis (p < 0.05). DRP-1 effects in melanoma differ from those seen in other cancer cells. These results provide new insights into BCL-2 family’s regulation of the apoptotic pathway in melanoma, and suggest that inhibiting the major anti-apoptotic proteins is sufficient to induce cell death even without involvement from major pro-apoptotic proteins. Importantly, our study also indicates that DRP-1 inhibition is a promising adjuvant for BH3 mimetics in melanoma treatment.

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“…By inhibiting MCL-1, A-1210477 was shown to interact synergistically with the BCL-2/BCL-xL inhibitor ABT-263 (navitoclax) to kill a variety of cancer cell types (34)(35)(36). We found that the combination of A-1210477 and cobimetinib was synergistic as shown by a mechanism that involved disruption of the interaction of MCL-1 with the pro-apoptotic BH3-only proteins BIM and BAK by A-1210477, and by the ability of cobimetinib to suppress MCL-1 and induce BIM expression.…”

Section: Discussionmentioning

confidence: 99%

Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer.

Kawakami

Huang

Pal

et al. 2017

JCO

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Oncogenic BRAF V600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer (CRC). In BRAF V600E mutant CRCs, treatment failure may be related to BRAF V600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAF V600E can upregulate antiapoptotic MCL-1 in a gene dose-dependent manner using CRC cell lines isogenic for BRAF. BRAF V600E -induced MCL-1 upregulation was confirmed by ectopic BRAF V600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1 Thr163 ) and stabilize MCL-1. Upregulation of MCL-1 was mediated by MEK/ERK shown by the ability of ERK siRNA to suppress MCL-1. Stabilization of MCL-1 by phosphorylation was shown by a phosphorylationmimicking mutant and an unphosphorylated MCL-1 mutant that decreased or increased MCL-1 protein turnover, respectively. MEK/ERK inhibition by cobimetinib suppressed MCL-1 expression/phosphorylation and induced pro-apoptotic BIM to a greater extent than did vemurafenib in BRAF V600E cell lines. MCL-1 knockdown vs control shRNA significantly enhanced cobimetinib-induced apoptosis in vitro and in HT29 colon cancer xenografts. The small molecule MCL-1 inhibitor, A-1210477 also enhanced cobimetinib-induced apoptosis in vitro that was due to disruption of the interaction of MCL-1 with pro-apoptotic BAK and BIM. Knockdown of BIM attenuated BAX, but not BAK, activation by cobimetinib plus A-1210477. In summary, BRAF V600E -mediated MEK/ERK activation can upregulate MCL-1 by phosphorylation/ stabilization to confer apoptosis resistance that can be reversed by MCL-1 antagonism combined with cobimetinib, suggesting a novel therapeutic strategy against BRAF V600E mutant CRCs.

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MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

Cited by 108 publications

References 46 publications

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors

BH3 mimetics induce apoptosis independent of DRP-1 in melanoma

Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer.

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