2. Academic Validation
  3. Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition

Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition

  • Mol Cancer Ther. 2021 Jan;20(1):64-75. doi: 10.1158/1535-7163.MCT-20-0259.
Tatiana Shorstova 1,  Jie Su 1,  Tiejun Zhao 1,  Michael Dahabieh 1,  Matthew Leibovitch 1,  Mariana De Sa Tavares Russo 2,  Daina Avizonis 2,  Shivshankari Rajkumar 3,  Ian R Watson 3,  Sonia V Del Rincón 1,  Wilson H Miller Jr 1,  William D Foulkes 1 4,  Michael Witcher 5
Affiliations

Affiliations

  • 1 Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.
  • 2 Goodman Cancer Research Centre's (GCRC) Metabolomics Facility, McGill University, Montreal, Quebec, Canada.
  • 3 Department of Biochemistry, Goodman Research Centre, McGill University, Montreal, Quebec, Canada.
  • 4 Departments of Oncology and Human Genetics, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.
  • 5 Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada. michael.witcher@mcgill.ca.
PMID: 33087508 DOI: 10.1158/1535-7163.MCT-20-0259
Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal Cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of Cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK Inhibitor cobimetinib to repress the proliferation of SCCOHT in vivo Notably, this synergy is also observed in some SMARCA4-expressing ovarian adenocarcinoma models intrinsically resistant to BETi. Mass spectrometry, coupled with knockdown of newly found targets such as Thymidylate Synthase, revealed that the repression of a panel of proteins involved in nucleotide synthesis underlies this synergy both in vitro and in vivo, resulting in reduced pools of nucleotide metabolites and subsequent cell-cycle arrest. Overall, our data indicate that dual treatment with BETi and MEKi represents a rational combination therapy against SCCOHT and potentially additional ovarian Cancer subtypes.

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