Mcl-1 deficiency results in peri-implantation embryonic lethality

Rinkenberger, Julie L.; Horning, Susan; Klocke, Barbara J.; Roth, Kevin A.; Korsmeyer, Stanley J.

doi:10.1101/gad.14.1.23

Cited by 345 publications

(40 citation statements)

References 35 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the observation that MCL-1 deletion is lethal in knockout mice (45) and previous reports pointing to a crucial physiological role for MCL-1 in many cell types including cardiomyocytes (46,47), we found that the administration of S63845 was well tolerated, in agreement with a recent report (29). This may be due to partial inhibition of MCL-1 in the adult rather than complete deletion during critical developmental time points.…”

Section: Discussionsupporting

confidence: 84%

Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 84%

Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In hESCs, MCL1 promotes the maintenance of stem cell pluripotency by regulating the mitochondrial dynamics of stem cells [ 27 ]. MCL1 knockout mice were shown to have trophectoderm defects that resulted in peri-implantation embryonic lethality [ 36 ], consistent with the impaired ability of the IDs KO cells in this study to differentiate into TSCs. In-depth analysis suggested that ID1 and ID3 promote the expression of MCL1 by inhibiting TCF3 and that MCL1 promotes AKT phosphorylation through direct interaction.…”

Section: Discussionsupporting

confidence: 83%

ID proteins promote the survival and primed-to-naive transition of human embryonic stem cells through TCF3-mediated transcription

Jiang

et al. 2022

Cell Death Dis

View full text Add to dashboard Cite

Inhibition of DNA binding proteins 1 and 3 (ID1 and ID3) are important downstream targets of BMP signalling that are necessary for embryonic development. However, their specific roles in regulating the pluripotency of human embryonic stem cells (hESCs) remain unclear. Here, we examined the roles of ID1 and ID3 in primed and naive-like hESCs and showed that ID1 and ID3 knockout lines (IDs KO) exhibited decreased survival in both primed and naive-like state. IDs KO lines in the primed state also tended to undergo pluripotent dissolution and ectodermal differentiation. IDs KO impeded the primed-to-naive transition (PNT) of hESCs, and overexpression of ID1 in primed hESCs promoted PNT. Furthermore, single-cell RNA sequencing demonstrated that ID1 and ID3 regulated the survival and pluripotency of hESCs through the AKT signalling pathway. Finally, we showed that TCF3 mediated transcriptional inhibition of MCL1 promotes AKT phosphorylation, which was confirmed by TCF3 knockdown in KO lines. Our study suggests that IDs/TCF3 acts through AKT signalling to promote survival and maintain pluripotency of both primed and naive-like hESCs.

show abstract

“…Indirect MCL-1 targeting strategies may be particularly important from a translational perspective because direct targeting of MCL-1 gives rise to rapid therapeutic resistance in vitro. Furthermore, there are currently no bioavailable inhibitors that have been demonsrated to target MCL-1 in humans, and a body of literature suggests that such agents may be difficult to tolerate owing to MCL-1's physiological essentiality, its role in hematopoietic stem cell survival, and its potential roles outside of mitochondrial apoptosis regulation (47,48).…”

Section: Discussionmentioning

confidence: 99%

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

et al. 2016

View full text Add to dashboard Cite

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that the combined inhibition of BCL-XL and the mTOR/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses MCL-1 protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL. This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of molecular subtype or PIK3CA mutational status. Further, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to anti-apoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard of care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

show abstract

Mcl-1 deficiency results in peri-implantation embryonic lethality

Cited by 345 publications

References 35 publications

Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

ID proteins promote the survival and primed-to-naive transition of human embryonic stem cells through TCF3-mediated transcription

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

Contact Info

Product

Resources

About