Pharmacogenetics of BCR/ABL Inhibitors in Chronic  Myeloid Leukemia

Polillo, Marialuisa; Galimberti, Sara; Baratè, Claudia; Petrini, Mario; Danesi, Romano; Paolo, Antonello Di

doi:10.3390/ijms160922811

Cited by 31 publications

(23 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BCR-ABL in chronic myelogenous leukemia; mutated active ERBB1 in non-small cell lung cancer; mutated active B-RAF in melanoma; the majority of other tumor types and subtypes have a pleiotropic combination of mutations in tumor promoters and tumor suppressors that collectively facilitate tumorigenesis: e.g. in breast cancer; head and neck cancer; liver cancer [ 4 – 6 ]. It is even possible, as we note in the associated companion manuscripts, that tumor material upon standard of care screening does not present with any of the known well defined mutations in proteins linked to tumorigenesis in that tumor type; e.g.…”

Section: Introductionmentioning

confidence: 99%

The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling

et al. 2016

View full text Add to dashboard Cite

We generated afatinib resistant clones of H1975 lung cancer cells by transient exposure of established tumors to the drug and collected the re-grown tumors. Afatinib resistant H1975 clones did not exhibit any additional mutations in proto-oncogenes when compared to control clones. Afatinib resistant H1975 tumor clones expressed less PTEN than control clones and in afatinib resistant clones this correlated with increased basal SRC Y416, ERBB3 Y1289, AKT T308 and mTOR S2448 phosphorylation, decreased expression of ERBB1, ERBB2 and ERBB3 and increased total expression of c-MET, c-KIT and PDGFRβ. Afatinib resistant clones were selectively killed by knock down of [ERBB3 + c-MET + c-KIT] but not by the individual or doublet knock down combinations. The combination of the ERBB1/2/4 inhibitor afatinib with the SRC family inhibitor dasatinib killed afatinib resistant H1975 cells in a greater than additive fashion; other drugs used in combination with dasatinib such as sunitinib, crizotinib and amufatinib were less effective. [Afatinib + dasatinib] treatment profoundly inactivated ERBB3, AKT and mTOR in the H1975 afatinib resistant clones and increased ATG13 S318 phosphorylation. Knock down of ATG13, Beclin1 or eIF2α strong suppressed killing by [ERBB3 + c-MET + c-KIT] knock down, but were only modestly protective against [afatinib + dasatinib] lethality. Thus afatinib resistant H1975 NSCLC cells rely on ERBB1- and SRC-dependent hyper-activation of residual ERBB3 and elevated signaling, due to elevated protein expression, from wild type c-MET and c-KIT to remain alive. Inhibition of ERBB3 signaling via both blockade of SRC and ERBB1 results in tumor cell death.

show abstract

Section: Introductionmentioning

confidence: 99%

The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In agreement with what observed for ABCB1 , we did not find any clinical impact for the hOCT1 polymorphism on nilotinib efficacy and tolerability; this result was already expected, because it is well known that nilotinib is more lipophilic than imatinib and in vitro experiments suggested that it is not substrate for the hOCT1 influx transporter [ 32 ]. Other studies investigated the substrate affinity of nilotinib for other transmembrane transporters, but conclusive results are not yet achieved [ 33 ]. The lack of any significant effect of hOCT1 and ABCB1 polymorphisms on the achievement of cytogenetic and molecular responses or on the EFS could be particularly relevant in the clinical practice.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, in contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.

show abstract

“…Most TKIs are transported by P-gp and BCRP, thus polymorphisms in genes encoding these transporters are likely to influence the pharmacokinetics of TKIs. Most studied in this respect is the first approved TKI; imatinib, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors [ 115 ]. However, conflicting results have been reported as to whether ABCB1/ABCG2 polymorphisms affect the pharmacokinetics of imatinib [ 116 – 122 ].…”

Section: Drug Transportersmentioning

confidence: 99%

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

2016

View full text Add to dashboard Cite

Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.

show abstract

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

Cited by 31 publications

References 90 publications

The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling

The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling

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

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

Contact Info

Product

Resources

About