Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias

As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also...

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Bibliographic Details
Published in:	Blood Vol. 122; no. 17; pp. 3034 - 3044
Main Authors:	Walker, Christopher J., Oaks, Joshua J., Santhanam, Ramasamy, Neviani, Paolo, Harb, Jason G., Ferenchak, Gregory, Ellis, Justin J., Landesman, Yosef, Eisfeld, Ann-Kathrin, Gabrail, Nash Y., Smith, Carrie L., Caligiuri, Michael A., Hokland, Peter, Roy, Denis Claude, Reid, Alistair, Milojkovic, Dragana, Goldman, John M., Apperley, Jane, Garzon, Ramiro, Marcucci, Guido, Shacham, Sharon, Kauffman, Michael G., Perrotti, Danilo
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 24-10-2013 American Society of Hematology
Subjects:	Adult Animals Antigens, CD34 - genetics Antigens, CD34 - metabolism Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Proliferation - drug effects Clinical Trials, Phase I as Topic DNA-Binding Proteins Drug Evaluation, Preclinical Exportin 1 Protein Fusion Proteins, bcr-abl - antagonists & inhibitors Fusion Proteins, bcr-abl - genetics Fusion Proteins, bcr-abl - metabolism Gene Expression Regulation, Leukemic - drug effects Histone Chaperones - antagonists & inhibitors Histone Chaperones - genetics Histone Chaperones - metabolism Humans Hydrazines - pharmacology Karyopherins - antagonists & inhibitors Karyopherins - genetics Karyopherins - metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology Male Mice Myeloid Neoplasia Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Protein Kinase Inhibitors - pharmacology Protein Transport Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Ribonucleoproteins - antagonists & inhibitors Ribonucleoproteins - genetics Ribonucleoproteins - metabolism Transcription Factors - antagonists & inhibitors Transcription Factors - genetics Transcription Factors - metabolism Triazoles - pharmacology
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Summary:	As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also known as chromosome maintenance protein 1, regulates cell growth and differentiation by controlling the nucleocytoplasmic trafficking of proteins and RNAs, some of which are aberrantly modulated in BCR-ABL1+ leukemias. Using CD34+ progenitors from CML, B-ALL, and healthy individuals, we found that XPO1 expression was markedly increased, mostly in a TKI-sensitive manner, in CML-BC and Ph+ B-ALL. Notably, XPO1 was also elevated in Ph− B-ALL. Moreover, the clinically relevant XPO1 inhibitor KPT-330 strongly triggered apoptosis and impaired the clonogenic potential of leukemic, but not normal, CD34+ progenitors, and increased survival of BCR-ABL1+ mice, 50% of which remained alive and, mostly, became BCR-ABL1 negative. Moreover, KPT-330 compassionate use in a patient with TKI-resistant CML undergoing disease progression significantly reduced white blood cell count, blast cells, splenomegaly, lactate dehydrogenase levels, and bone pain. Mechanistically, KPT-330 altered the subcellular localization of leukemia-regulated factors including RNA-binding heterogeneous nuclear ribonucleoprotein A1 and the oncogene SET, thereby inducing reactivation of protein phosphatase 2A tumor suppressor and inhibition of BCR-ABL1 in CML-BC cells. Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph+ leukemias. •XPO1/CRM1 is upregulated in a BCR-ABL1 kinase-dependent and -independent manner and negatively controls PP2A tumor suppressor activity.•KPT-330 antagonizes survival of TKI-resistant Ph+ acute leukemias in vitro, in CML-BC animals, and in a CML-AP patient.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2013-04-495374