The <i>hOCT1</i> and <i>ABCB1</i> polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia

Galimberti, Sara; Bucelli, Cristina; Arrigoni, E.; Baratè, Claudia; Grassi, Susanna; Ricci, Federica; Guerrini, Francesca; Ciabatti, Elena; Fava, Carmen; D’Avolio, Antonio; Fontanelli, Giulia; Cambrin, Giovanna Rege; Isidori, Alessandro; Loscocco, Federica; Caocci, Giovanni; Greco, Marianna; Bocchia, Monica; Aprile, Lara; Gozzini, Antonella; Scappini, Barbara; Cattaneo, Daniele; Scortechini, Anna Rita; Nasa, Giorgio La; Bosi, Alberto; Leoni, Pietro; Danesi, Romano; Saglio, Giuseppe; Visani, Giuseppe; Cortelezzi, Agostino; Petrini, Mario; Iurlo, Alessandra; Paolo, Antonello Di

doi:10.18632/oncotarget.21406

Cited by 14 publications

(13 citation statements)

References 39 publications

(45 reference statements)

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“…Because the role of CD34+/CD38–/CD26+ leukemic cells and pharmacogenetic/pharmacogenomic aspects have been already discussed in some of our previous works (7–20), in this study we focused on the gene expression profiling, in order to evaluate if de-regulation of some candidate genes at early time-points of therapy could impact on the clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms of several transmembrane drug transporters. They can be predictive of response or intolerance in CML patients: indeed, it has been demonstrated that single nucleotide polymorphisms (SNP) of hOCT1, ABCB1, and ABCG2 conditioned the imatinib pharmacokinetics and disposition whereas they did not impact on Nilotinib efficacy or toxicity (16–20). This could be relevant in the decision of which kind of TKI has to be prescribed in the first line.…”

Section: Introductionmentioning

confidence: 99%

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The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

et al. 2019

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Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a “real-life” setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were “resistant;” after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a “low” up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a “high” gene over-expression ( p = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a “low” up-regulation were event-free vs. 33% of those who presented a “high” gene expression ( p = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

et al. 2019

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“…Hence, TKIs function by binding to ATP-binding catalytic sites of the TK domains on RTKs or on non-RTKs, thereby, preventing TK phosphorylation and inhibiting down-stream intracellular signaling and transcription of genes such as pro-inflammatory cytokines. TKIs can also bind and occupy ATP- or substrate-binding sites on transmembrane transporters such as the hOTC1 influx protein and the ABC efflux pumps ( 64 – 66 ), thereby, affecting drug and cellular responses (right hand panel). RTK, receptor tyrosine kinase; TK, tyrosine kinase; hOCT1, human organic cation transport member 1; ABC, ATP-binding cassette; ABCB1, ABC sub-family B member 1 (P-glycoprotein 1); ATP, adenosine triphosphate; ADP, adenosine diphosphate; p, phosphate; NDB1, nucleotide binding domain 1; NDB2, nucleotide binding domain 2; TMD1, transmembrane domain 1; TMD2, transmembrane domain 2; TKI, tyrosine kinase inhibitor.…”

Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

“…TKIs can also bind and occupy ATP- or substrate-binding sites on transmembrane transporters, such as the ATP-binding cassette (ABC) efflux pumps and the human organic cation transport member 1 (hOTC1) influx protein ( 64 – 66 ) thereby affecting drug and cellular responses ( Figure 2 , right hand panel). In CML, TKIs such as imatinib and dasatinib, have been shown to not only target and inhibit BCR-ABL1, but also c-KIT, PDGF receptor (PDGFR), and Src family kinases, which results in the abrogation of the transcription of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, and prevents the proliferation of myeloid cells ( 70 ).…”

Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

et al. 2020

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Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.

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“…CML patients carrying the OCT1 c.480G allelic variant have lower clearance of imatinib than patients homozygous for the c.480C allelic variant [ 154 ]. However, clinical data indicates that CML patients with OCT1 polymorphisms that were negatively related with imatinib efficacy had no impact on nilotinib efficacy or toxicity [ 155 ].…”

Section: Slc22 Genetic Heterogeneity In Cancer Pharmacologymentioning

confidence: 99%

Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition

Lozano

Briz

Macı́as

et al. 2018

JPM

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An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient.

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The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia

Cited by 14 publications

References 39 publications

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition

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