The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
M
M
López-Guerra
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
S
S
Xargay-Torrent
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
L
L
Rosich
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
A
A
Montraveta
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
J
J
Roldán
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
A
A
Matas-Céspedes
Hematopathology Unit, Department of Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
N
N
Villamor
Hematopathology Unit, Department of Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
M
M
Aymerich
Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo - IUOPA, Oviedo, Spain.
C
C
López-Otín
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
P
P
Pérez-Galán
Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
G
G
Roué
Hematopathology Unit, Department of Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
E
E
Campo
1] Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain [2] Hematopathology Unit, Department of Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
D
D
Colomer
D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051881:Receptor, Notch1 / Q000235:genetics*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D013764:Tetrahydronaphthalenes; D053829:Amyloid Precursor Protein Secretases; D014740:Vidarabine; D014633:Valine; C024352:fludarabine; C550722:nirogacestat