Novel drug candidates for blast phase chronic myeloid leukemia from high-throughput drug sensitivity and resistance testing.
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.
Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
P O
PO
Pietarinen
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
T
T
Pemovska
Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
M
M
Kontro
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
B
B
Yadav
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
J P
JP
Mpindi
Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
E I
EI
Andersson
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
M M
MM
Majumder
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
H
H
Kuusanmäki
Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
P
P
Koskenvesa
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
O
0000000232310332
O
Kallioniemi
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
K
K
Wennerberg
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
C A
CA
Heckman
Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
S
S
Mustjoki
Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
K
K
Porkka
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001752:Blast Crisis / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents