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Nature Reviews. Drug Discovery Jul 2021Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we... (Review)
Review
Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we review the remarkable progress made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001. These compounds have had a significant impact on the way in which we now treat cancers and non-cancerous conditions. We discuss how the challenge of drug resistance to kinase inhibitors is being met and the future of kinase drug discovery.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Discovery; Drug Resistance, Neoplasm; Humans; Imatinib Mesylate; Protein Kinase Inhibitors
PubMed: 34002056
DOI: 10.1038/s41573-021-00195-4 -
Hematology. American Society of... Nov 2018June 2018 was the 20th anniversary of the clinical use of the first tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia. Since then, the change in... (Review)
Review
June 2018 was the 20th anniversary of the clinical use of the first tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia. Since then, the change in prognosis for patients with this disease is one of the major success stories of modern cancer medicine. The dilemmas that face physicians and patients are no longer only those concerned with delaying inevitable progression to the terminal blastic phase or selecting the individuals most likely to benefit from allogeneic stem-cell transplantation; rather, they are now focused also on the choice of TKI, the management of comorbidities and adverse effects, strategies to improve quality of life, and the appropriateness of a trial of therapy discontinuation. Interestingly, with 4 TKIs approved for frontline use, the choice of initial therapy continues to cause controversy, a situation made more complicated by the tantalizing prospect of treatment-free remission. In this manuscript, we will explore the factors influencing this decision and try to provide a pragmatic and clinically applicable solution.
Topics: Clinical Trials as Topic; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Quality of Life
PubMed: 30504305
DOI: 10.1182/asheducation-2018.1.161 -
The New England Journal of Medicine Mar 2017Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy.
METHODS
In this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events.
RESULTS
The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment.
CONCLUSIONS
Almost 11 years of follow-up showed that the efficacy of imatinib persisted over time and that long-term administration of imatinib was not associated with unacceptable cumulative or late toxic effects. (Funded by Novartis Pharmaceuticals; IRIS ClinicalTrials.gov numbers, NCT00006343 and NCT00333840 .).
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cross-Over Studies; Cytarabine; Cytogenetic Analysis; Female; Follow-Up Studies; Humans; Imatinib Mesylate; Intention to Treat Analysis; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Protein Kinase Inhibitors; Survival Analysis; Young Adult
PubMed: 28273028
DOI: 10.1056/NEJMoa1609324 -
The European Respiratory Journal Dec 2022Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT)...
BACKGROUND
Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib.
METHODS
Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416/H model were performed.
RESULTS
Seralutinib potently inhibited PDGFRα/β, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry in human lung PAH samples demonstrated increased PDGFR, CSF1R and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2.
CONCLUSIONS
Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.
Topics: Rats; Humans; Animals; Pulmonary Arterial Hypertension; Imatinib Mesylate; Monocrotaline; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Pulmonary Artery; Protein Kinase Inhibitors; Hypoxia; MicroRNAs; Disease Models, Animal
PubMed: 35680144
DOI: 10.1183/13993003.02356-2021 -
Molecular Therapy : the Journal of the... Feb 2023Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management....
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.
Topics: Humans; Gemcitabine; Imatinib Mesylate; Deoxycytidine; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Signal Transduction; Drug Resistance, Neoplasm
PubMed: 36384875
DOI: 10.1016/j.ymthe.2022.11.004 -
Gastroenterology Mar 2024Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to...
BACKGROUND & AIMS
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities.
METHODS
Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models.
RESULTS
Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis.
CONCLUSIONS
Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.
Topics: Humans; Animals; Mice; Gastrointestinal Stromal Tumors; Antineoplastic Agents; Proteomics; Imatinib Mesylate; Cell Line, Tumor; Disease Models, Animal; Gastrointestinal Neoplasms; Serine-Arginine Splicing Factors
PubMed: 37995868
DOI: 10.1053/j.gastro.2023.11.284 -
Cancer Research and Treatment Jan 2020Although imatinib-induced hepatotoxicity may aggravate the patient's clinical condition and alter the treatment plan, the underlying mechanism of and factors influencing...
PURPOSE
Although imatinib-induced hepatotoxicity may aggravate the patient's clinical condition and alter the treatment plan, the underlying mechanism of and factors influencing imatinibinduced hepatotoxicity have rarely been investigated. The purpose of this study was to investigate factors affecting on the incidence of hepatotoxicity within 90 days after starting imatinib treatment and time to onset of imatinib-induced hepatotoxicity.
MATERIALS AND METHODS
We retrospectively evaluated the records of 177 patients receiving imatinib from October 2012 to September 2017. The analyzed factors included sex, age, body weight, body surface area, underlying disease, and concomitant drugs.
RESULTS
The proportion of patients with hepatotoxicity within 90 days after imatinib administration was 33.9%. Proton pump inhibitors (PPIs) increased the incidence of hepatotoxicity approximately 3.8-fold and doubled the hazard of time to reach hepatotoxicity. Patients with liver disease or hepatitis B virus (HBV) carriers had a more than 8-fold higher risk of hepatotoxicity and a 5.2-fold increased hazard of hepatotoxicity compared to those without liver disease or HBV. Patients with body weight under 55 kg had a 2.2-fold higher risk for occurrence of hepatotoxicity. Patients with an imatinib dose > 400 mg had a 2.3-fold increased hazard of time to reach hepatotoxicity compared to those with an imatinib dose ≤ 400 mg.
CONCLUSION
The findings of this study suggest that the use of PPIs and presence of liver disease or HBV were associated with imatinib-induced hepatotoxicity. Thus, close liver function monitoring is recommended, especially in patients with liver impairment or using PPIs.
Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Chemical and Drug Induced Liver Injury; Female; Humans; Imatinib Mesylate; Male; Middle Aged; Neoplasms; Odds Ratio; Prognosis; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 31291714
DOI: 10.4143/crt.2019.131 -
Cell Death and Differentiation Feb 2023Secondary resistance to imatinib (IM) represents a major challenge for therapy of gastrointestinal stromal tumors (GISTs). Aberrations in oncogenic pathways, including...
N-methyladenosine-modified USP13 induces pro-survival autophagy and imatinib resistance via regulating the stabilization of autophagy-related protein 5 in gastrointestinal stromal tumors.
Secondary resistance to imatinib (IM) represents a major challenge for therapy of gastrointestinal stromal tumors (GISTs). Aberrations in oncogenic pathways, including autophagy, correlate with IM resistance. Regulation of autophagy-related protein 5 (ATG5) by the ubiquitin-proteasome system is critical for autophagic activity, although the molecular mechanisms that underpin reversible deubiquitination of ATG5 have not been deciphered fully. Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. USP13 preferentially is induced in GIST cells by IM and interacts with ATG5, which leads to stabilization of ATG5 through deubiquitination. Activation of PAK1 promoted phosphorylation of ATG5 thereby enhancing the interaction of ATG5 with USP13. Furthermore, N-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the mA reader IGF2BP2. Moreover, an inhibitor of USP13 caused ATG5 decay and co-administration of this inhibitor with 3-methyladenine boosted treatment efficacy of IM in murine xenograft models derived from GIST cells. Our findings highlight USP13 as an essential regulator of autophagy and IM resistance in GIST cells and reveal USP13 as a novel potential therapeutic target for GIST treatment.
Topics: Humans; Animals; Mice; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Autophagy-Related Protein 5; Autophagy; Drug Resistance, Neoplasm; Methyltransferases; RNA-Binding Proteins; Ubiquitin-Specific Proteases
PubMed: 36528756
DOI: 10.1038/s41418-022-01107-8 -
Journal of Hematology & Oncology Jul 2022Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI),... (Review)
Review
Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR::ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians' international and personal experiences, may give insight into alternative approaches not previously considered.
Topics: Antineoplastic Agents; COVID-19; Dasatinib; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pandemics; Protein Kinase Inhibitors
PubMed: 35818053
DOI: 10.1186/s13045-022-01309-0 -
International Journal of Molecular... Oct 2022The receptor tyrosine kinase inhibitor imatinib improves patient cancer survival but is linked to cardiotoxicity. This study investigated imatinib's effects on cell...
The receptor tyrosine kinase inhibitor imatinib improves patient cancer survival but is linked to cardiotoxicity. This study investigated imatinib's effects on cell viability, apoptosis, autophagy, and necroptosis in human cardiac progenitor cells in vitro. Imatinib reduced cell viability (75.9 ± 2.7% vs. 100.0 ± 0.0%) at concentrations comparable to peak plasma levels (10 µM). Imatinib reduced cells' TMRM fluorescence (74.6 ± 6.5% vs. 100.0 ± 0.0%), consistent with mitochondrial depolarisation. Imatinib increased lysosome and autophagosome content as indicated by LAMP2 expression (2.4 ± 0.3-fold) and acridine orange fluorescence (46.0 ± 5.4% vs. 9.0 ± 3.0), respectively. Although imatinib increased expression of autophagy-associated proteins and also impaired autophagic flux, shown by proximity ligation assay staining for LAMP2 and LC3II (autophagosome marker): 48 h of imatinib treatment reduced visible puncta to 2.7 ± 0.7/cell from 11.3 ± 2.1 puncta/cell in the control. Cell viability was partially recovered by autophagosome inhibition by wortmannin, with the viability increasing 91.8 ± 8.2% after imatinib-wortmannin co-treatment (84 ± 1.5% after imatinib). Imatinib-induced necroptosis was associated with an 8.5 ± 2.5-fold increase in mixed lineage kinase domain-like pseudokinase activation. Imatinib-induced toxicity was rescued by RIP1 inhibition: 88.6 ± 3.0% vs. 100.0 ± 0.0% in the control. Imatinib applied to human cardiac progenitor cells depolarises mitochondria and induces cell death through necroptosis, recoverable by RIP1 inhibition, with a partial role for autophagy.
Topics: Acridine Orange; Apoptosis; Autophagy; Cell Death; Humans; Imatinib Mesylate; Protein Kinase Inhibitors; Stem Cells; Wortmannin
PubMed: 36233113
DOI: 10.3390/ijms231911812