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Published on: January 18, 2017
A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer
Caigang Liu1, Yixiao Zhang2, Jiujiao Gao3
1Department of Oncology, Cancer Stem Cell and Translational Medicine Lab, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Abstract:
Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.
Insights
A new drug, LFS-1107, effectively targets and eliminates breast cancer stem-like cells (BCSCs) in triple-negative breast cancer (TNBC). This exportin-1 antagonist shows promise in preclinical models for treating TNBC by overcoming drug resistance and preventing recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Breast cancer stem-like cells (BCSCs) drive recurrence, metastasis, and drug resistance in triple-negative breast cancer (TNBC).
- Targeting BCSCs is crucial for effective TNBC treatment.
Purpose of the Study:
- To discover and evaluate LFS-1107, a novel small-molecule antagonist of exportin-1, as a potential therapeutic agent against TNBC.
- To investigate the mechanism of action and efficacy of LFS-1107 in preclinical TNBC models.
Main Methods:
- Nuclear export functional assays, bio-layer interferometry, and mutant cell line analysis to identify exportin-1 as the target of LFS-1107.
- In vitro studies on TNBC cell lines and CD44+CD24- enriched BCSCs.
- In vivo studies using mouse xenograft models and patient-derived tumor organoids (PDTOs).
Main Results:
- LFS-1107 selectively eliminated CD44+CD24- enriched BCSCs at nanomolar concentrations.
- LFS-1107 induced nuclear retention of Survivin, suppressed STAT3 transactivation, and downregulated stemness regulators.
- LFS-1107 inhibited TNBC tumor growth in vivo, eradicated residual BCSCs, and showed superior efficacy against PDTOs compared to approved drugs.
- LFS-1107 enhanced chemotherapy effects and reduced multidrug resistance markers.
Conclusions:
- LFS-1107 is a potent exportin-1 antagonist with selective activity against BCSCs in TNBC.
- LFS-1107 demonstrates significant preclinical efficacy in inhibiting tumor growth and overcoming drug resistance.
- LFS-1107 represents a promising therapeutic candidate for depleting BCSCs in TNBC treatment.
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