Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (selinexor), a first in class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the anti-tumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid organ cancers ex vivo and in vivo. The K+CS combination was not toxic to non-malignant cells as compared to malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared to KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51 and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of PARP inhibitors further potentiates the K+CS anti-tumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

中文翻译：

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水杨酸盐通过 S 期阻滞和受损的 DNA 损伤修复增强 CRM1 抑制剂的抗肿瘤活性

染色体区域维持蛋白1 (CRM1) 介导细胞核蛋白输出，是抗癌治疗的新靶点。KPT-330（selinexor）是一种首创的 CRM1 抑制剂，最近被批准用于复发性多发性骨髓瘤和弥漫性大 B 细胞淋巴瘤，但其更广泛的应用受到严重毒性的限制。我们发现水杨酸盐通过将作用机制扩展到 CRM1 抑制之外，显着增强了 CRM1 抑制剂的抗肿瘤活性。联合使用水杨酸盐能够以低得多的 selinexor 剂量靶向一系列血癌，从而有可能减轻令人望而却步的临床副作用。水杨酸胆碱 (CS) 与低剂量 KPT-330 (K+CS) 对离体和体内的高危血液恶性肿瘤和实体器官癌具有有效、广泛的活性。与恶性细胞相比，K+CS 组合对非恶性细胞没有毒性，并且是安全的，不会对小鼠的正常器官产生毒性。机制上，与单独的 KPT-330 相比，K+CS 抑制 CRM1、Rad51 和胸苷酸合酶蛋白的表达，从而更有效地抑制 CRM1 介导的核输出、DNA 损伤修复受损、嘧啶合成减少、细胞周期停滞S期，细胞凋亡。此外，加入 PARP 抑制剂可进一步增强 K+CS 的抗肿瘤作用。K+CS 代表了一种针对多种类型血癌的新型疗法，并将激发未来的研究，以利用 DNA 损伤修复和核质转运进行一般的癌症治疗。