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ABSTRACT: Imatinib mesylate (IM), a tyrosine kinase inhibitor, is one of the first molecularly targeted therapies to have been used
in the clinic. It has proven to be efficient in the treatment of chronic myeloid leukemia and also in other malignancies that
involve expression of a tyrosine kinase. However, some patients can develop resistance and others suffer from toxic side effects.
The pharmacokinetics of IM depends on several enzymes and transporters, and several studies have attempted to identify genetic
factors associated with variable drug levels and clinical responses using a candidate gene approach. Larger and more homogenous
studies are still needed to replicate the findings obtained so far, or to analyze other genetic variations to get clearer
insights into how IM treatment can be tailored to each patient's genetics. Here we summarize pharmacogenetic studies of IM
and highlight the genetic markers that could be used to improve the treatment and management of diseases for which IM is used.
Genome Medicine 04/2012; 2(11):1-8.
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ABSTRACT: In this study, we have addressed how Lyn kinase signaling mediates nilotinib-resistance by quantitative phospho-proteomics using Stable Isotope Labeling with Amino acid in Cell culture. We have found an increased tyrosine phosphorylation of 2 additional tyrosine kinases in nilotinib-resistant cells: the spleen tyrosine kinase Syk and the UFO family receptor tyrosine kinase Axl. This increased tyrosine phosphorylation involved an interaction of these tyrosine kinases with Lyn. Inhibition of Syk by the inhibitors R406 or BAY 61-3606 or by RNA interference restored the capacity of nilotinib to inhibit cell proliferation. Conversely, coexpression of Lyn and Syk were required to fully induce resistance to nilotinib in drug-sensitive cells. Surprisingly, the knockdown of Syk also strongly decreased tyrosine phosphorylation of Lyn and Axl, thus uncovering interplay between Syk and Lyn. We have shown the involvement of the adaptor protein CDCP-1 in resistance to nilotinib. Interestingly, the expression of Axl and CDCP1 were found increased both in a nilotinib-resistant cell line and in nilotinib-resistant CML patients. We conclude that an oncogenic signaling mediated by Lyn and Syk can bypass the need of Bcr-Abl in CML cells. Thus, targeting these kinases may be of therapeutic value to override imatinib or nilotinib resistance in CML.
Blood 07/2011; 118(8):2211-21. · 9.90 Impact Factor
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Pharmacogenomics 09/2010; 11(9):1201-3. · 3.97 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Imatinib mesylate (IM), a tyrosine kinase inhibitor, is one of the first molecularly targeted therapies to have been used in the clinic. It has proven to be efficient in the treatment of chronic myeloid leukemia and also in other malignancies that involve expression of a tyrosine kinase. However, some patients can develop resistance and others suffer from toxic side effects. The pharmacokinetics of IM depends on several enzymes and transporters, and several studies have attempted to identify genetic factors associated with variable drug levels and clinical responses using a candidate gene approach. Larger and more homogenous studies are still needed to replicate the findings obtained so far, or to analyze other genetic variations to get clearer insights into how IM treatment can be tailored to each patient's genetics. Here we summarize pharmacogenetic studies of IM and highlight the genetic markers that could be used to improve the treatment and management of diseases for which IM is used.
Genome Medicine 01/2010; 2(11):85.
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Fidaa Al-Shakfa, Stéphanie Dulucq,
Ivan Brukner,
Iva Milacic,
Marc Ansari,
Patrick Beaulieu,
Albert Moghrabi,
Caroline Laverdière,
Stephen E Sallan,
Lewis B Silverman,
Donna Neuberg,
Jeffery L Kutok,
Daniel Sinnett,
Maja Krajinovic
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ABSTRACT: Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. We recently reported an association of DHFR promoter polymorphisms with ALL outcome. Lower event-free survival correlated with haplotype *1, defined by A(-317) and C(-1610) alleles. Haplotype *1 was also associated higher DHFR expression.
Here, we analyzed adjacent 400-bp region participating in DHFR regulation as both a major promoter and a noncoding minor transcript.
Six polymorphisms were identified, of which five were single nucleotide polymorphisms and one was length polymorphism composed of variable number of 9-bp elements and 9-bp insertion/deletion. Haplotype analysis including all promoter polymorphisms revealed diversification of haplotype *1 into five subtypes (*1a-*1e). DNA variations of major promoter/noncoding transcript region and haplotype *1 subtypes were subsequently analyzed for the association with ALL outcome. Lower event-free survival was associated with an A allele of G(308)A polymorphism (P = 0.02) and with *1b haplotype (P = 0.01). This association was particularly striking in high-risk patients (P = 0.001) and was subsequently confirmed in independent patient cohort (P = 0.02). Haplotype *1b was the only haplotype *1 subtype associated with higher mRNA levels.
The study provides a new insight into DHFR regulatory variations predisposing to an event in ALL patients.
Clinical Cancer Research 10/2009; 15(22):6931-8. · 7.74 Impact Factor
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ABSTRACT: Despite the excellent efficacy of imatinib in chronic myeloid leukemia (CML), the response in patients is heterogeneous, which may in part be caused by pharmacogenetic variability. Imatinib has been reported to be a substrate of the P-glycoprotein pump. In the current study, we focused on the ABCB1 (MDR1) genotype. We analyzed the 3 most relevant single nucleotide polymorphisms of MDR1 in 90 CML patients treated with imatinib. Among the patients homozygous for allele 1236T, 85% achieved a major molecular response versus 47.7% for the other genotypes (P = .003). For the 2677G>T/A polymorphism, the presence of G allele was associated with worse response (77.8%, TT/TA; vs 47.1%, GG/GA/GT; P = .018). Patients with 1236TT genotype had higher imatinib concentrations. One of the haplotypes (1236C-2677G-3435C) was statistically linked to less frequent major molecular response (70% vs 44.6%; P = .021). Hence, we demonstrated the usefulness of these single nucleotide polymorphisms in the identification of CML who may or may not respond optimally to imatinib.
Blood 09/2008; 112(5):2024-7. · 9.90 Impact Factor
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ABSTRACT: Dihydrofolate reductase (DHFR) is the major target of methotrexate (MTX), a key component in childhood acute lymphoblastic leukemia (ALL) treatment. A total of 15 polymorphisms in DHFR promoter were analyzed, and 3 sites (C-1610G/T, C-680A, and A-317G) were identified as sufficient to define observed haplotypes (tag single nucleotide polymorphisms [tagSNPs]). These polymorphisms were investigated for association with treatment response in 277 children with ALL. Lower event-free survival (EFS) was associated with homozygosity for the allele A-317 and C-1610 (P=.03 and .02), and with the haplotype *1, defined by both C-1610 and A-317 alleles (P=.03). The haplotype *1 conferred higher transcriptional activity (P<.01 compared with haplotypes generating minimal luciferase expression). Quantitative mRNA analysis showed higher DHFR levels for particular haplotype *1 carriers (P<.01). The analysis combining haplotype *1 with thymidylate synthase (TS) and cyclin D1 (CCND1) genotypes previously shown to affect ALL outcome showed that the number of event-predisposing genotypes was associated with increasingly lower EFS (P<.001). In conclusion, DHFR promoter polymorphisms are associated with worse ALL outcome, likely due to a higher DHFR expression. Combined effects among genes of the folate cycle can further accentuate differences in the response to the treatment.
Blood 04/2008; 111(7):3692-700. · 9.90 Impact Factor
