Dasatinib plus Nutlin-3 shows synergistic anti-leukemic activity in both p53wild-type and p53mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway.

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Dasatinib plus Nutlin-3 shows synergistic anti-leukemic activity in both

p53wild-type and p53mutated B chronic lymphocytic leukemias by inhibiting the

Akt pathway.

G Zauli, R Voltan, R Bosco, E Melloni, S Marmiroli, GM Rigolin, A Cuneo, and P

Secchiero

Clin. Cancer Res., November 24, 2010;

Morphology and Embryology, University of Ferrara.

PURPOSE: To analyze the effect of the combination of Dasatinib, a multi-kinase

inhibitor, plus Nutlin-3, a non-genotoxic activator of the p53 pathway, in

primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic

cell line models.EXPERIMENTAL DESIGN: The induction of cytotoxicity was

evaluated in both primary B-CLL cell samples (n=20) and in p53wild-type (EHEB,

JVM-2) and p53deleted/mutated (MEC-2, BJAB) B leukemic cell lines. The role of

Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or

Dasatinib+Nutlin-3 was documented by functional experiments carried out using

specific pharmacological inhibitors and by over-expression of membrane-targeted

constitutively active form of Akt.RESULTS: The combination of Dasatinib+Nutlin-3

exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL

samples, including patients carrying 17p- (n=4), and in both p53wild-type and

p53deleted/mutated B leukemic cell lines. At the molecular level, Dasatinib

significantly counteracted the Nutlin-3-mediated induction of the p53

transcriptional targets MDM2 and p21 observed in p53wild-type leukemic cells.

Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease

the phosphorylation levels of ERK1/2, p38/MAPK and Akt in both p53wild-type and

p53deleted/mutated B leukemic cell lines. A critical role of Akt down-regulation

in mediating the anti-leukemic activity of Dasatinib and Dasatinib+Nutlin-3 was

demonstrated in experiments carried out by specifically modulating the Akt

pathway. CONCLUSIONS: These findings suggest that Dasatinib+Nutlin-3 might

represent an innovative therapeutic combination for both p53wild-type and

p53deleted/mutated B-CLL.

PMID: 21106726

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