Novel drug candidates for blast phase chronic myeloid leukemia from high-throughput drug sensitivity and resistance testing.

P O Pietarinen,K Wennerberg,M M Majumder,C A Heckman,S Mustjoki,T Pemovska,K Porkka,H Kuusanmäki,P Koskenvesa,B Yadav,E I Andersson,O Kallioniemi,J P Mpindi,M Kontro

doi:10.1038/bcj.2015.30

Abstract

Chronic myeloid leukemia in blast crisis (CML BC) remains a challenging disease to treat despite the introduction and advances in tyrosine kinase inhibitor (TKI) therapy. In this study we set out to identify novel candidate drugs for CML BC by using an unbiased high-throughput drug testing platform. We used three CML cell lines representing different types of CML blast phases (K562, EM-2 and MOLM-1) and primary leukemic cells from three CML BC patients. Profiling of drug responses was performed with a drug sensitivity and resistance testing platform comprising 295 anticancer agents. Overall, drug sensitivity scores and the drug response profiles of cell line and primary cell samples correlated well and were distinct from other types of leukemia samples. The cell lines were highly sensitive to TKIs and the clinically TKI-resistant patient samples were also resistant ex vivo. Comparison of cell line and patient sample data identified new candidate drugs for CML BC, such as vascular endothelial growth factor receptor and nicotinamide phosphoribosyltransferase inhibitors. Our results indicate that these drugs in particular warrant further evaluation by analyzing a larger set of primary patient samples. The results also pave way for designing rational combination therapies.

Highlights

Tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) is arguably the best example of successful targeted cancer treatment
Our results indicate that both primary Chronic myeloid leukemia in blast crisis (CML blast crisis (BC)) and cell line samples display a unique drug sensitivity pattern, which differs from other leukemia types
All cell lines proliferated at similar rates during the 72 h incubation period predetermined number to ensure that each was in growth phase at the

Summary

Introduction

Tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) is arguably the best example of successful targeted cancer treatment. The discovery of the Philadelphia chromosome and the role of BCR-ABL1 kinase in CML pathogenesis led to the development of the first approved TKI imatinib, which has remarkably improved the prognosis and survival of CML patients.[1] Imatinib is widely used as a first-line therapy together with second-generation TKIs dasatinib and nilotinib, which are applicable as second-line therapy for patients who become resistant or intolerant to imatinib.[2,3]. Despite the treatment breakthroughs in chronic phase CML, advanced phase and blast crisis (BC) remain a therapeutic challenge.[4] Owing to the more aggressive nature of advanced phase CML, patients tend to respond less favorably to TKI treatment. There is a clear need for identification of novel drug therapies for CML BC patients

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Results

Conclusion