In vitro validation of gamma-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia.
BACKGROUND
Activating NOTCH1 mutations are common in T-cell acute lymphoblastic leukemia. Inhibition of NOTCH1 signaling with gamma-secretase inhibitors causes cell cycle block, but only after treatment for several days. We further documented the effects of gamma-secretase inhibitor treatment on T-cell acute lymphoblastic leukemia cell lines and tested whether combining gamma-secretase inhibitors with other anti-cancer drugs offers a therapeutic advantage.


METHODS
The effect of gamma-secretase inhibitor treatment and combinations of gamma-secretase inhibitors with chemotherapy or glucocorticoids was assessed on T-cell acute lymphoblastic leukemia cell lines. We sequenced NOTCH1 in T-cell acute lymphoblastic leukemia cases with ABL1 fusions and tested combinations of gamma-secretase inhibitors and the ABL1 inhibitor imatinib in a T-cell acute lymphoblastic leukemia cell line.


RESULTS
gamma-secretase inhibitor treatment for 5-7 days reversibly inhibited cell proliferation, caused cell cycle block in sensitive T-cell acute lymphoblastic leukemia cell lines, and caused differentiation of some T-cell acute lymphoblastic leukemia cell lines. Treatment for 14 days or longer was required to induce significant apoptosis. The cytotoxic effects of the chemotherapeutic agent vincristine were not significantly enhanced by addition of gamma-secretase inhibitors to T-cell acute lymphoblastic leukemia cell lines, but gamma-secretase inhibitor treatment sensitized cells to the effect of dexamethasone. NOTCH1 mutations were identified in all T-cell acute lymphoblastic leukemia patients with ABL1 fusions and in a T-cell acute lymphoblastic leukemia cell line expressing NUP214-ABL1. In this cell line, the anti-proliferative effect of imatinib was increased by pre-treatment with gamma-secretase inhibitors.


CONCLUSIONS
Short-term treatment of T-cell acute lymphoblastic leukemia cell lines with gamma-secretase inhibitors had limited effects on cell proliferation and survival. Combinations of gamma-secretase inhibitors with other drugs may be required to obtain efficient therapeutic effects in T-cell acute lymphoblastic leukemia, and not all combinations may be useful.
De Keersmaecker
Kim
K
Human Genome Laboratory, Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium.
Lahortiga
Idoya
I
Mentens
Nicole
N
Folens
Cedric
C
Van Neste
Leander
L
Bekaert
Sofie
S
Vandenberghe
Peter
P
Odero
Maria D
MD
Marynen
Peter
P
Cools
Jan
J
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001570:Benzodiazepinones / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D004273:DNA, Neoplasm / Q000235:genetics; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D017422:Sequence Analysis, DNA; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology
C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D000970:Antineoplastic Agents; D001549:Benzamides; D001570:Benzodiazepinones; D002219:Carbamates; D004273:DNA, Neoplasm; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; C497761:NOTCH1 protein, human; C521114:NUP214-ABL1 fusion protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D051881:Receptor, Notch1; D014750:Vincristine; D003907:Dexamethasone; D000068877:Imatinib Mesylate; D053829:Amyloid Precursor Protein Secretases; D003630:Daunorubicin