Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells.
Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-α or PI3K-γ, respectively. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation.
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.|Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases University of Cologne, Cologne, Germany.
Elisa
E
Göckeritz
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.
Susan
S
Kerwien
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.
Michael
M
Baumann
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.
Marion
M
Wigger
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.|Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases University of Cologne, Cologne, Germany.
Verena
V
Vondey
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.|Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases University of Cologne, Cologne, Germany.
Lars
L
Neumann
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.
Thomas
T
Landwehr
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.
Clemens M
CM
Wendtner
Roche Pharmaceutical Research & Early Development, Roche Innovation Center Zurich, Switzerland.
Christian
C
Klein
Bayer HealthCare Pharmaceuticals, Global Drug Discovery, TRG Oncology, Berlin, Germany.
Ningshu
N
Liu
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.|Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases University of Cologne, Cologne, Germany.
Michael
M
Hallek
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.|Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases University of Cologne, Cologne, Germany.
Lukas P
LP
Frenzel
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, Cologne, Germany.|Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases University of Cologne, Cologne, Germany.
Günter
G
Krause
D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D000069283:Rituximab; D015398:Signal Transduction
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D007527:Isoenzymes; D007546:Isoquinolines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines; D011799:Quinazolines; D052999:Quinazolinones; D000069283:Rituximab; C515255:CXCL12 protein, human; C586691:duvelisib; C000589253:copanlisib; C552946:idelalisib
apoptosis; chronic lymphocytic leukemia; kinase inhibitors; monoclonal antibodies