A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells

Elsevier

Available online 20 November 2022, 100903

Drug Resistance UpdatesAuthor links open overlay panelAbstract

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.

AbbreviationsBCSC

breast cancer stem-like cells

TNBC

triple-negative breast cancer

PDTOs

patient-derived tumor organoids

SPR

surface plasmon resonance

MFA

mammosphere formation assay

IHC

immunohistochemical staining analysis

PBS

phosphate-buffered saline

CRM1

chromosomal maintenance 1

STAT3

signal transducer and activator of transcription 3

TCGA

the cancer genome atlas

Keywords

breast cancer stem cells

CRM1

STAT3

natural compounds

drug resistance

© 2022 The Authors. Published by Elsevier Ltd.

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