The role of bosutinib in the treatment of chronic myeloid leukemia

The availability of several BCR-ABL1 tyrosine kinase inhibitor (TKI) options means physicians and patients can select the most appropriate treatment for a patient with chronic myeloid leukemia (CML). BCR-ABL TKI selection as a first- or later-line therapy is dependent on a number of clinical factors. Regular monitoring of patients, patient education, dose optimization and management of treatment-emergent adverse events are key aspects of long-term chronic myeloid leukemia management and contribute to improved clinical outcomes, quality of life, patient adherence and healthcare costs. This review provides an overview of the BCR-ABL1 TKI bosutinib, its pharmacology and clinical trials; discusses the impact of comorbidities and concomitant medications on bosutinib treatment selection; and suggests strategies for managing adverse events and dose optimization during bosutinib treatment

Locking Src/Abl Tyrosine Kinase Activities Regulate Cell Differentiation and Invasion of Human Cervical Cancer Cells Expressing E6/E7 Oncoproteins of High-Risk HPV

In this study, we compared the effects of SKI-606 with Iressa, Src/Abl and EGF-R kinase inhibitors, respectively, on selected parameters in HeLa and SiHa cervical cancer cell lines, which express E6/E7 oncoproteins of high-risk HPV types 18 and 16, respectively. Our results show that SKI-606 and Iressa inhibit cell proliferation and provoke G0-G1 cell cycle arrest and reduction of S and G2-M phase using 2 and 5 μM concentrations of these inhibitors. In contrast, SKI-606 induces differentiation to an epithelial phenotype “mesenchymal-epithelial transition”; thus SKI-606 causes a dramatic decrease in cell motility and invasion abilities of HeLa and SiHa cancer cells, in comparison to untreated cells and Iressa-treated cells in which these parameters are only slightly affected. These changes are accompanied by a regulation of the expression patterns of E-cadherin and catenins. The molecular pathway analysis of Src/Abl inhibitor revealed that SKI-606 blocks the phosphorylation of β-catenin and consequently converts its role from a transcriptional regulator to a cell-cell adhesion molecule. Our findings indicate that SKI-606 inhibits signaling pathways involved in regulating tumor cell migration and invasion genes via β-catenin alteration, suggesting that Src inhibitor, in comparison to EGF-R, is a promising therapeutic agent for human cervical cancer

Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase

a b s t r a c t RET kinase is aberrantly activated in thyroid cancers and in rare cases of lung and colon cancer, and has been validated as a molecular target in these tumors. Vandetanib was recently approved for the treatment of medullary thyroid cancer. However, vandetanib is ineffective in vitro against RET mutants carrying bulky aminoacids at position 804, the gatekeeper residue, similarly to drug-resistant BCR-ABL mutants in chronic myeloid leukemia. Ponatinib is a multi-target kinase inhibitor that was recently approved for treatment-refractory Philadelphia-positive leukemia. We show here potent inhibition of oncogenic RET by ponatinib, including the drug-insensitive V804M/L mutants. Ponatinib inhibited the growth of RET+ and BCR-ABL+ cells with similar potency, while not affecting RET-negative cells. Both in biochemical and in cellular assays ponatinib compared favorably with known RET inhibitors, such as vandetanib, cabozantinib, sorafenib, sunitinib and motesanib, used as reference compounds. We suggest that ponatinib should be considered for the treatment of RET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations

In Vivo Eradication of Human BCR/ABL-Positive Leukemia Cells With an ABLKinase Inhibitor

BACKGROUND: The leukemia cells of approximately 95% of patients with chronic myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic leukemia express the Bcr/Abl oncoprotein, which is the product of a fusion gene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncoprotein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineoplastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase. METHODS: Nude mice were given an injection of the Bcr/Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice were treated intraperitoneally or orally with CGP57148B according to three different schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the in vivo treatment schedule. RESULTS: Treatment schedules administering CGP57148B once or twice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial (>50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours was defined as the duration of continuous exposure needed to block cell proliferation and to induce apoptosis in these two leukemia cell lines. A treatment regimen assuring the continuous block of the Bcr/Abl phosphorylating activity that was administered over an 11-day period cured 87%-100% of treated mice. CONCLUSION: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in viv

Rapid recognition of drug-resistance/sensitivity in leukemic cells by Fourier transform infrared microspectroscopy and unsupervised hierarchical cluster analysis

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Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance

Role of α1 Acid Glycoprotein in the In Vivo Resistance of Human BCR-ABL+ Leukemic Cells to the Abl Inhibitor STI571

Background: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. Methods: Nude mice were injected with KU812 Bcr-Abl+ human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. Results: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein α1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P<.001) were observed after the combination treatment. Conclusion: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this dru

Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias

Abstract Background The purpose of the study was to assess renal function in patients with Philadelphia chromosome-positive leukemias receiving bosutinib or imatinib. Patients and Methods Patients received first-line bosutinib (n = 248) or imatinib (n = 251; phase III trial), or second-line or later bosutinib (phase I/II trial; n = 570). Adverse events (AEs) and changes from baseline in estimated glomerular filtration rate (eGFR) and serum creatinine were assessed. Results Time from the last patient's first dose to data cutoff was ≥ 48 months. Renal AEs were reported in 73/570 patients (13%) receiving second-line or later bosutinib, and in 22/248 (9%) and 16/251 (6%) receiving first-line bosutinib and imatinib, respectively. eGFR in patients receiving bosutinib declined over time with more patients developing Grade ≥ 3b eGFR ( 2 according to the Modification of Diet in Renal Disease method) with second-line or later bosutinib (139/570, 24%) compared with first-line bosutinib (26/248, 10%) and imatinib (25/251, 10%); time to Grade ≥ 3b eGFR was shortest with second-line or later bosutinib. Similar proportions of patients receiving second-line or later bosutinib (74/139, 53%), first-line bosutinib (15/26, 58%), and first-line imatinib (15/25, 60%) improved to ≥ 45 mL/min/1.73 m 2 eGFR as of the last follow-up. In a regression analysis, first-line treatment with bosutinib versus imatinib was not a significant predictor of Grade ≥ 3b eGFR. Conclusion Long-term bosutinib treatment is associated with an apparently reversible decline in renal function with frequency and characteristics similar to renal decline observed with long-term imatinib treatment. Patients with risk factors for Grade ≥ 3b eGFR should be monitored closely