selinexor and olaparib

CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Disease Models, Animal; Female; High-Throughput Screening Assays; Humans; Hydrazines; Mice; Mice, Nude; Ovarian Neoplasms; Phthalazines; Piperazines; Triazoles

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer 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 antitumor 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 nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with 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 poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor 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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Choline; DNA Repair; DNA Replication; DNA, Neoplasm; Drug Combinations; Drug Synergism; Exportin 1 Protein; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Phthalazines; Piperazines; Random Allocation; Receptors, Cytoplasmic and Nuclear; S Phase Cell Cycle Checkpoints; Salicylates; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays