CRM1 inhibitor anti-tumor activity is enhanced with salicylates by S-phase arrest and impaired DNA-damage repair.

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. Copyright © 2020 American Society of Hematology.

Citation

Jithma Abeykoon, Xiaosheng Wu, Kevin Edward Nowakowski, Surendra Dasari, Jonas Paludo, S John Weroha, Chunling Hu, Xiaonan Hou, Jann N Sarkaria, Ann C Mladek, Jessica Lynne Phillips, Andrew Feldman, Aishwarya Ravindran, Rebecca L King, Justin C Boysen, Mary Stenson, Ryan M Carr, Michelle K Manske, Julian R Molina, Prashant Kapoor, Sameer A Parikh, Shaji K Kumar, Steven I Robinson, Jia Yu, Judy C Boughey, Liewei Wang, Matthew P Goetz, Fergus J Couch, Mrinal M Patnaik, Thomas E Witzig. CRM1 inhibitor anti-tumor activity is enhanced with salicylates by S-phase arrest and impaired DNA-damage repair. Blood. 2020 Nov 02

PMID: 33140103

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