Advances in Small-Molecule Drug Discovery for Triple-Negative Breast Cancer

Fosu-Mensah, Nelly; Peris, María Sánchez; Weeks, Hoi Ping; Cai, Jun; Westwell, Andrew D.

doi:10.4155/fmc.15.129

Cited by 18 publications

(14 citation statements)

References 127 publications

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“… 36 Meanwhile, systemic cytotoxic chemotherapy has major drawbacks including toxicological side effects and drug resistance. 37 These factors make options for TNBC particularly problematic. In this study, small-molecule RL71 targeting SERCA2 showed strong anti-cancer activity on TNBC cells mainly by triggering excessive autophagy both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer

et al. 2017

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Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca2+ from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment.

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Section: Discussionmentioning

confidence: 99%

Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer

et al. 2017

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“… 2 Though only ~15–20% of all breast cancers are diagnosed as basal-like/triple-negative (referred to herein for simplicity as TNBC), TNBC disproportionately affects young premenopausal women, as well as women of African descent, and is difficult to treat. 3 , 4 These tumors are also associated with a poor prognosis, high recurrence risk, and poor disease-free survival relative to other breast cancer subtypes. In fact, the median survival of patients with metastatic TNBC is just 13 months, and almost all patients with metastatic TNBC die in spite of treatment with systemic chemotherapy, the only treatment option currently available due to a lack of validated, actionable molecular targets for therapy.…”

Section: Introductionmentioning

confidence: 99%

Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers

et al. 2017

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Basal-like/triple-negative breast cancers (TNBC) are among the most aggressive forms of breast cancer and disproportionally affecting young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts (PDX). Thus, our data identify EphA2 as a novel molecular target for TNBC.

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“…Despite some initial success, most of the agents have shown only limited efficacy in both preclinical and clinical settings. Therefore, only a few of them are advanced into clinical trials for the treatment of TNBC patients [10].…”

Section: Ivyspringmentioning

confidence: 99%

Mifepristone Derivative FZU-00,003 Suppresses Triple-negative Breast Cancer Cell Growth partially via miR-153-KLF5 axis

Liu¹,

Chen²,

Zhao³

et al. 2020

Int. J. Biol. Sci.

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Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers lacking targeted therapeutics currently. We recently reported that mifepristone (MIF), a drug regularly used for abortion, suppresses TNBC cell growth by inhibiting KLF5 expression via inducing miR-153. However, its anticancer efficacy is only modest at high dose. In order to enhance the anticancer activities, a focused compound library containing 17 compounds by altering the sensitive metabolic region of mifepristone has been designed and synthesized. We first tested the cell growth inhibitory effects of these compounds in TNBC cell lines. Among them, FZU-00,003 displayed the most potent efficiency. FZU-00,003 suppresses TNBC cell growth, cell cycle progression and induces apoptosis more effectively than MIF does. Consistently, FZU-00,003 induces miR-153 expression and suppressed KLF5 expression at much lower dosages than MIF does. Furthermore, FZU-00,003 inhibits tumor growth more potently than MIF does. Taken together, the MIF derivative, FZU-00,003 may serve as a better therapeutic compound for TNBC than MIF.

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Advances in Small-Molecule Drug Discovery for Triple-Negative Breast Cancer

Cited by 18 publications

References 127 publications

Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer

Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer

Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers

Mifepristone Derivative FZU-00,003 Suppresses Triple-negative Breast Cancer Cell Growth partially via miR-153-KLF5 axis

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