2. Academic Validation
  3. Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan

Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan

  • NPJ Breast Cancer. 2023 Aug 11;9(1):66. doi: 10.1038/s41523-023-00573-8.
Ming Zhao 1,  Timothy P DiPeri 2,  Maria Gabriela Raso 3,  Xiaofeng Zheng 4,  Yasmeen Qamar Rizvi 1,  Kurt W Evans 1,  Fei Yang 3,  Argun Akcakanat 1,  Marco Roberto Estecio 5,  Debu Tripathy 6,  Ecaterina E Dumbrava 1,  Senthil Damodaran 6,  Funda Meric-Bernstam 7 8
Affiliations

Affiliations

  • 1 Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Bioinformatics and Computational Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Epigenetic and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Department of Breast Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. fmeric@mdanderson.org.
  • 8 Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. fmeric@mdanderson.org.
PMID: 37567892 DOI: 10.1038/s41523-023-00573-8
Abstract

TROP2 antibody drug conjugates (ADCs) are under active development. We seek to determine whether we can enhance activity of TROP2 ADCs by increasing TROP2 expression. In metaplastic breast cancers (MpBC), there is limited expression of TROP2, and downregulating transcription factor ZEB1 upregulates E-cad and TROP2, thus sensitizing cancers to TROP2 ADC sacituzumab govitecan (SG). Demethylating agent decitabine decreases DNA Methyltransferase expression and TROP2 promoter methylation and subsequently increases TROP2 expression. Decitabine treatment as well as overexpression of TROP2 significantly enhance SG antitumor activity. Decitabine also increases SLFN11, a biomarker of Topoisomerase 1 inhibitor (TOP1) sensitivity and is synergistic with SG which has a TOP1 payload, in TROP2-expressing SLFN11-low BC cells. In conclusion, TROP2 and SLFN11 expression can be epigenetically modulated and the combination of demethylating agent decitabine with TROP2 ADCs may represent a novel therapeutic approach for tumors with low TROP2 or SLFN11 expression.

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