American Association for Cancer Research
15357163mct200259-sup-240553_2_supp_6577333_qgq2y1.pdf (117.9 kB)

Figure S4 from Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition

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journal contribution
posted on 2023-04-03, 18:23 authored by Tatiana Shorstova, Jie Su, Tiejun Zhao, Michael Dahabieh, Matthew Leibovitch, Mariana De Sa Tavares Russo, Daina Avizonis, Shivshankari Rajkumar, Ian R. Watson, Sonia V. del Rincón, Wilson H. Miller, William D. Foulkes, Michael Witcher

Cell cycle analysis after BETi/cobimetinib exposure in OVCAR4 cells


Canadian Institute for Health Research



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.