DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer

Hetakshi Kurani, Seyedeh Fatemeh Razavipour, Kuzhuvelil B. Harikumar, Matthew Dunworth, Andrew J. Ewald, Apsra Nasir, Gray Pearson, Derek Van Booven, Zhiqun Zhou, Diana Azzam, Claes Wahlestedt, Joyce Slingerland

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: Although chemotherapies kill most cancer cells, stem cell–enriched survivors seed metastasis, particularly in triple-negative breast cancers (TNBC). TNBCs arise from and are enriched for tumor stem cells. Here, we tested if inhibition of DOT1L, an epigenetic regulator of normal tissue stem/progenitor populations, would target TNBC stem cells. Experimental Design: Effects of DOT1L inhibition by EPZ-5676 on stem cell properties were tested in three TNBC lines and four patient-derived xenograft (PDX) models and in isolated cancer stem cell (CSC)-enriched ALDH1+ and ALDH1- populations. RNA sequencing compared DOT1L regulated pathways in ALDH1+ and ALDH1- cells. To test if EPZ-5676 decreases CSC in vivo, limiting dilution assays of EPZ-5676/vehicle pretreated ALDH1+ and ALDH1- cells were performed. Tumor latency, growth, and metastasis were evaluated. Antitumor activity was also tested in TNBC PDX and PDX-derived organoids. Results: ALDH1+ TNBC cells exhibit higher DOT1L and H3K79me2 than ALDH1-. DOT1L maintains MYC expression and self-renewal in ALDH1+ cells. Global profiling revealed that DOT1L governs oxidative phosphorylation, cMyc targets, DNA damage response, and WNT activation in ALDH1+ but not in ALDH1- cells. EPZ-5676 reduced tumorspheres and ALDH1+ cells in vitro and decreased tumor-initiating stem cells and metastasis in xenografts generated from ALDH1+ but not ALDH1- populations in vivo. EPZ-5676 significantly reduced growth in vivo of one of two TNBC PDX tested and decreased clonogenic 3D growth of two other PDX-derived organoid cultures. Conclusions: DOT1L emerges as a key CSC regulator in TNBC. Present data support further clinical investigation of DOT1L inhibitors to target stem cell–enriched TNBC.

Original languageEnglish (US)
Pages (from-to)1948-1965
Number of pages18
JournalClinical Cancer Research
Volume28
Issue number9
DOIs
StatePublished - May 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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