Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias.

Dany A Curi,Nicholas J Donato,Gavin T Blyth,Leonidas C Platanias,Elspeth M Beauchamp,Francis J Giles,Ahmet Dirim Arslan,Jessica K Altman

doi:10.18632/oncotarget.5091

Abstract

We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias. We provide evidence that inhibition of PIM, with the pan-PIM inhibitor SGI-1776, results in suppression of classic PIM effectors and also elements of the mTOR pathway, suggesting interplay between PIM and mTOR signals. Our data demonstrate that PIM inhibition enhances the effects of imatinib mesylate on Ph+ leukemia cells. We also found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate. Importantly, inhibition of PIM results in enhanced suppression of primary leukemic progenitors from patients with CML. Altogether these findings suggest that pharmacological PIM targeting may provide a unique therapeutic approach for the treatment of Ph+ leukemias.

Highlights

Chronic myelogenous leukemia (CML) evolves from abnormal hematopoietic stem cells of myeloid origin
We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias
We found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate

Summary

Introduction

Chronic myelogenous leukemia (CML) evolves from abnormal hematopoietic stem cells of myeloid origin. Its signature characteristic is the genetic translocation, t(9;22) (q34;q11) BCR-ABL1, known as the Philadelphia chromosome (Ph+) [1, 2] This abnormality is found in about 90 to 95% of CML, approximately 25% of adult acute lymphoblastic leukemia (ALL), and 3 to 4% of cases of pediatric ALL [1, 2]. Significant adverse effects have been reported with these latter agents, and a significant number of patients treated with ponatinib have developed severe thrombosis and/or vascular occlusive disease [5, 9]. These difficulties in the management of patients with refractory Ph+ leukemias underscore the need to develop novel agents and unique therapeutic approaches to overcome resistance to BCR-ABL1 TKIs

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Conclusion