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Protein biomarkers for response to XPO1 inhibition in haematologic malignancies |
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| Authors: | Tulasigeri M Totiger Sana Chaudhry Elgilda Musi Jumana Afaghani Skye Montoya Frank Owusu-Ansah Stanley Lee Gary Schwartz Virginia Klimek Justin Taylor |
| Institution: | 1. Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida, USA
Contribution: ?Investigation (lead), Writing - original draft (equal);2. Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida, USA Contribution: ?Investigation (supporting), Writing - review & editing (equal);3. Columbia University School of Medicine, New York, New York, USA Contribution: ?Investigation (supporting), Writing - review & editing (equal);4. Memorial Sloan Kettering Cancer Center, New York, New York, USA Contribution: ?Investigation (supporting), Writing - review & editing (equal);5. Fred Hutchinson Cancer Center, Seattle, Washington, USA Contribution: ?Investigation (supporting), Writing - review & editing (equal);6. Columbia University School of Medicine, New York, New York, USA Contribution: Conceptualization (supporting), Supervision (equal), Writing - review & editing (equal);7. Memorial Sloan Kettering Cancer Center, New York, New York, USA Contribution: Conceptualization (supporting), Supervision (equal), Writing - review & editing (equal);8. Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida, USA |
| Abstract: | XPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumour and haematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes, not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using haematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision-making in the personalized treatment of cancer patients undergoing treatment with selinexor. |
| Keywords: | exportin-1 haematologic malignancies nuclear export protein biomarker protein cargoes XPO1 inhibition XPO1 mutation |