XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53-p21 and p27 pathways

Nitin Chakravarti; Amy Boles; Rachel Burzinski; Paola Sindaco; Colleen Isabelle; Kathleen McConnell; Anjali Mishra; Pierluigi Porcu

doi:10.1038/s41598-024-59994-5

XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53-p21 and p27 pathways

Sci Rep. 2024 Apr 23;14(1):9305. doi: 10.1038/s41598-024-59994-5.

Authors

Nitin Chakravarti¹, Amy Boles², Rachel Burzinski², Paola Sindaco², Colleen Isabelle², Kathleen McConnell², Anjali Mishra², Pierluigi Porcu³

Affiliations

¹ Division of Hematologic Malignancies, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, BLSB 328, Philadelphia, PA, 19107, USA. nitin.chakravarti@jefferson.edu.
² Division of Hematologic Malignancies, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
³ Division of Hematologic Malignancies, Sidney Kimmel Cancer Center, Thomas Jefferson University, 834 Chestnut Street, Suite 320, Philadelphia, PA, 19107, USA. pierluigi.porcu@jefferson.edu.

Abstract

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in CTCL cells. KPT-330 reduces cell proliferation, induces G1 cell cycle arrest and apoptosis. RNA-sequencing was used to explore the underlying mechanisms. Genes associated with the cell cycle and the p53 pathway were significantly enriched with KPT-330 treatment. KPT-330 suppressed XPO1 expression, upregulated p53, p21^WAF1/Cip1, and p27^Kip1 and their nuclear localization, and downregulated anti-apoptotic protein (Survivin). The in vivo efficacy of KPT-330 was investigated using a bioluminescent xenograft mouse model of CTCL. KPT-330 blocked tumor growth and prolonged survival (p < 0.0002) compared to controls. These findings support investigating the use of KPT-330 and next-generation XPO1 inhibitors in CTCL.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Apoptosis* / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21* / genetics
Cyclin-Dependent Kinase Inhibitor p21* / metabolism
Cyclin-Dependent Kinase Inhibitor p27* / genetics
Cyclin-Dependent Kinase Inhibitor p27* / metabolism
Exportin 1 Protein*
Gene Expression Regulation, Neoplastic / drug effects
Humans
Hydrazines / pharmacology
Hydrazines / therapeutic use
Karyopherins* / antagonists & inhibitors
Karyopherins* / metabolism
Lymphoma, T-Cell, Cutaneous* / drug therapy
Lymphoma, T-Cell, Cutaneous* / genetics
Lymphoma, T-Cell, Cutaneous* / metabolism
Lymphoma, T-Cell, Cutaneous* / pathology
Mice
Receptors, Cytoplasmic and Nuclear* / antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear* / metabolism
Signal Transduction / drug effects
Triazoles* / pharmacology
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism
Xenograft Model Antitumor Assays

Substances

Exportin 1 Protein
Receptors, Cytoplasmic and Nuclear
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Tumor Suppressor Protein p53
selinexor
Karyopherins
Triazoles
Hydrazines
CDKN1A protein, human
TP53 protein, human
CDKN1B protein, human