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.

中文翻译：

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核苷酸代谢重编程介导表观遗传治疗和 MAP 激酶抑制之间的协同作用


高钙血症型卵巢小细胞癌 (SCCOHT) 是一种罕见但通常致命的癌症，诊断时的中位年龄为 24 岁。患者的最佳管理尚不明确，目前的治疗仍然具有挑战性，因此需要发现新的治疗方法。 SMARCA4 失活突变的鉴定总是表征这种类型的癌症，这为促进针对这种疾病的诊断和治疗措施提供了见解。我们在此表明​​，BET 抑制剂 OTX015 与 MEK 抑制剂 cobimetinib 协同作用，抑制 SCCOHT 体内增殖。值得注意的是，这种协同作用也在一些表达 SMARCA4 的卵巢腺癌模型中观察到，该模型对 BETi 具有内在耐药性。质谱分析，加上新发现的靶标（例如胸苷酸合酶）的敲除，揭示了对一组参与核苷酸合成的蛋白质的抑制是这种体外和体内协同作用的基础，导致核苷酸代谢物池减少和随后的细胞周期逮捕。总体而言，我们的数据表明，BETi 和 MEKi 双重治疗代表了针对 SCCOHT 和潜在其他卵巢癌亚型的合理联合疗法。