Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function

Campbell, Kirsteen J.; Mason, Susan; Winder, Matthew L.; Willemsen, Rosalie B. E.; Cloix, Catherine; Lawson, Hannah; Rooney, N.; Dhayade, Sandeep; Sims, Andrew H.; Blyth, Karen; Tait, Stephen W.G.

doi:10.1038/s41418-021-00773-4

Cited by 33 publications

(37 citation statements)

References 54 publications

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“…For instance, a recent study was published highlighting that the dependance of breast cancer on MCL1 expression was solely dependent on its apoptotic function. In the absence of BAK and BAX, genetic deletion of MCL1 has no impact on breast cancer cells 139 . This study highlights the importance of the BAK/BAX double knockout cell lines to fully disentangle many of these apoptotic versus non-apoptotic pathways in MCL1 regulation.…”

Section: Mcl1 Facilitates Mitochondrial Bioenergetics and Dynamicsmentioning

confidence: 99%

The multiple mechanisms of MCL1 in the regulation of cell fate

Widden

Placzek

2021

Commun Biol

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MCL1 (myeloid cell leukemia-1) is a widely recognized pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) family and a promising target for cancer therapy. While the role MCL1 plays in apoptosis is well defined, its participation in emerging non-apoptotic signaling pathways is only beginning to be appreciated. Here, we synthesize studies characterizing MCL1s influence on cell proliferation, DNA damage response, autophagy, calcium handling, and mitochondrial quality control to highlight the broader scope that MCL1 plays in cellular homeostasis regulation. Throughout this review, we discuss which pathways are likely to be impacted by emerging MCL1 inhibitors, as well as highlight non-cancerous disease states that could deploy Bcl-2 homology 3 (BH3)-mimetics in the future.

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Section: Mcl1 Facilitates Mitochondrial Bioenergetics and Dynamicsmentioning

confidence: 99%

The multiple mechanisms of MCL1 in the regulation of cell fate

Widden

Placzek

2021

Commun Biol

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“…Bak and Bax regulate the release of pro-apoptotic factors and are necessary for the execution of cell death. Bax/Bak-deficient tumors were shown to be resistant to Mcl-1 inhibition, whereas the presence of Bax/Bak in MCL1 -deficient mice resulted in long-term tumor suppression [ 140 ]. Apoptosis induction through Mcl-1 down-regulation in breast cancer cells was reliant on the activity of Bak, not Bax.…”

Section: Role Of Pro-apoptotic Proteins In Breast Cancer-mediated Cel...mentioning

confidence: 99%

Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy

Kawiak

Kostecka

2022

Cancers

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Estrogen receptor (ER)-positive breast cancer accounts for around two-thirds of breast cancer occurrences, with endocrine therapy serving as first-line therapy in most cases. Targeting estrogen signaling pathways, which play a central role in regulating ER+ breast cell proliferation and survival, has proven to improve patient outcomes. However, despite the undeniable advantages of endocrine therapy, a subset of breast cancer patients develop acquired or intrinsic resistance to ER-targeting agents, limiting their efficacy. The activation of downstream ER signaling pathways upregulates pro-survival mechanisms that have been shown to influence the response of cells to endocrine therapy. The Bcl-2 family proteins play a central role in cell death regulation and have been shown to contribute to endocrine therapy resistance, supporting the survival of breast cancer cells and enhancing cell death evasion. Due to the overexpression of anti-apoptotic Bcl-2 proteins in ER-positive breast cancer, the role of these proteins as potential targets in hormone-responsive breast cancer is growing in interest. In particular, recent advances in the development of BH3 mimetics have enabled their evaluation in preclinical studies with ER+ breast cancer models, and BH3 mimetics have entered early ER+ breast cancer clinical trials. This review summarizes the molecular mechanisms underlying the regulation of Bcl-2 family proteins in ER+ breast cancer. Furthermore, an overview of recent advances in research regarding the efficacy of BH3 mimetics in ER+ breast cancer has been provided.

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“…In vivo , S63845 illustrates single agent efficacy in restricting tumor growth in the MMTV-PyMT mouse model of breast cancer [ 118 ]. Combining S63845 with docetaxel in two TNBC PDX mouse models, or trastuzumab in a HER2 -amplified PDX mouse model, has been shown to significantly impair tumor growth and prolong survival, although monotherapy with the MCL-1 inhibitor failed to markedly prevent tumor growth [ 117 ].…”

Section: Pharmaceutical Targeting Of Mcl-1 With Bh3-mimeticsmentioning

confidence: 99%

“…The requirement for MCL-1 is exacerbated during 3-D tumoursphere growth in non-adherent culture conditions, where the functional redundancy often witnessed between MCL-1 and BCL-XL in 2-D monolayer growth is less profound [ 118 ]. Genetic knock-down or pharmacological blockade of MCL-1 also restricts the growth of TNBC cells (MDA-MB-468) in xenograft mouse models [ 45 , 120 ].…”

Section: Mcl-1 Is Required For Breast Cancer Cell Survivalmentioning

confidence: 99%

MCL-1 is a clinically targetable vulnerability in breast cancer

Winder

Campbell

2022

Cell Cycle

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Pro-survival members of the BCL-2 family, including MCL-1, are emerging as important proteins during the development and therapeutic response of solid tumors. Notably, high levels of MCL-1 occur in breast cancer, where functional dependency has been demonstrated using cell lines and mouse models. The utility of restoring apoptosis in cancer cells through inhibition of pro-survival BCL-2 proteins has been realized in the clinic, where the first specific inhibitor of BCL-2 is approved for use in leukemia. A variety of MCL-1 inhibitors are now undergoing clinical trials for blood cancer treatment and application of this new class of drugs is also being tested in solid cancers. On-target compounds specific to MCL-1 have demonstrated promising efficacy in preclinical models of breast cancer and show potential to enhance the anti-tumor effect of conventional therapies. Taken together, this makes MCL-1 an extremely attractive target for clinical evaluation in the context of breast cancer. Abbreviations: ADC (antibody-drug conjugate); AML (Acute myeloid leukemia); APAF1 (apoptotic protease activating factor 1); bCAFs (breast cancer associated fibroblasts); BCL-2 (B-cell lymphoma 2); BH (BCL-2 homology); CLL (chronic lymphocytic leukemia); EGF (epidermal growth factor); EMT (epithelial to mesenchymal transition); ER (estrogen receptor); FDA (food and drug administration); GEMM (genetically engineered mouse model); HER2 (human epidermal growth factor 2); IL6 (interleukin 6); IMM (inner mitochondrial membrane); IMS (intermembrane space); MCL-1 (myeloid cell leukemia-1); MOMP (mitochondrial outer membrane permeabilisation); MM (multiple myeloma); PDX (patient-derived xenograft); OMM (outer mitochondrial membrane); PROTAC (proteolysis-targeting chimeras) TNBC (triple negative breast cancer); UPS (ubiquitin mediated proteolysis system)

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Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function

Cited by 33 publications

References 54 publications

The multiple mechanisms of MCL1 in the regulation of cell fate

The multiple mechanisms of MCL1 in the regulation of cell fate

Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy

MCL-1 is a clinically targetable vulnerability in breast cancer

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