Imatinib resistance

Imatinib is, at present, the first-choice treatment for patients with chronic myeloid leukaemia in chronic phase. Despite the impressive rate of complete haematological response and complete cytogenetical remissions, some cases show primary resistance or relapse after an initial response (secondary or acquired resistance) Most results of imatinib resistance arise from experiences in GISTs and chronic myeloid leukemias (CMLs). A meta-analysis summarized 10 eligible studies that included 1083 GIST cases (Lee et al., 2013). Imatinib resistance was found in 35.5% of PDGFRA-mutant tumors, 27.4% of c-Kit-mutated tumors, and 33.7% of wild-type tumors (c-Kit and PDGFRA) An extensive search for molecules to block the aberrant BCR-ABL1 protein resulted in the development of IM as an orally bioavailable agent with remarkable efficacy in producing hematologic, cytogenetic, and molecular remissions GIST cells carrying KIT -del557-558/T670I or KIT -InsAY502-503/V654A mutations were resistant to imatinib, while PKC412 significantly inhibited autophosporylation of these mutants. Resistance to imatinib and sensitivity to PKC412 of KIT -T670I and PDGFRA -D842V mutants was confirmed using Ba/F3 cells

Imatinib resistance in CML - PubMe

  1. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P =.002)
  2. o acid 315 (Th315 to Ile315)
  3. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy
  4. Despite the outstanding success of the cancer drug imatinib, one obstacle in prolonged treatment is the emergence of resistance mutations within the kinase domain of its target, Abl. We noticed that many patient-resistance mutations occur in the dynamic hot spots recently identified to be responsible for imatinib's high selectivity toward Abl
  5. The amplification of the BCR-ABL gene or overexpression of bcr-abl protein kinase are two known mechanisms of relative resistance to imatinib34-36which could be overcome by dosages of 600 mg or 800 mg daily
  6. Because previous data had indicated a potential dose threshold phenomenon associated with imatinib-mediated enzyme inhibition, resistance may be an acquired phenomenon due to exposure of leukemia..
  7. Primary resistance to imatinib, defined as an inability to achieve landmark response, is comprised of the 2% of patients who fail to achieve hematologic response and 8-13% who fail to achieve major or complete cytogenetic response using early chronic phase CML treated with imatinib at diagnosis as a benchmark. 1 Strictly defining patients.

Resistance to imatinib encompasses failure to reach CHR, CCyR, and MMR within an allocated duration of time (primary resistance). A number of patients still do not succeed in obtaining a CHR, 20 to 25% do not achieve a CCyR (10), and fewer than 10% of patients achieve complete molecular response (CMR) (11) Imatinib resistance Although the majority of GIST patients achieve clinical benefit when treated with imatinib, approximately 10% will progress within 3 to 6 months of initiating therapy. Such cases are regarded as showing primary resistance to treatment It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this..

Imatinib Resistance - an overview ScienceDirect Topic

  1. The incidence of imatinib resistance has been increasingly detected in Eastern-Indian region after long term therapy with imatinib. However, the full scenario could not be depicted due to resource constraints. More numbers of patients are to be tested to achieve robust evidence
  2. Mechanisms of resistance to the tyrosine kinase inhibitor (TKI) imatinib had been modeled in vitro even prior to the first reports of clinical resistance in patients with chronic myeloid leukemia (CML)
  3. Intrinsic resistance to imatinib has been linked to rapid drug efflux from hematopoietic cells and inactivation of imatinib by binding to serum α1-acid glycoprotein, 9 although supporting in vivo.
  4. Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty.
  5. g resistant when it no longer responds to the drug (s) that are used to treat it. Most of these drugs belong to the class of tyrosine kinase inhibitors (TKI's.). These drugs bind to KIT and PDGFRα kinase receptors to silence the abnormal tumor growth signals
  6. The most common side effects include nausea, vomiting, diarrhea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite; weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), and edema

Imatinib resistance: obstacles and opportunities

Imatinib resistance was defined as a lack of complete hematologic response after 3 months of imatinib treatment, a lack of any cytogenetic response (Ph-positive cells, >95 percent) after 6 months. Resistance can be divided into primary resistance, or early progression, and secondary/delayed resistance, or late progression. The reported time intervals for early progression vary depending on the study, typically from 3 to 6 months [].In general, the tumor continues to progress despite initial exposure to imatinib Imatinib Resistance Mutation testing by NGS aids in: Full characterization of the spectrum of a minor (<20%) mutated variants. Ability to follow the dynamics of resistant mutations over time. Reconstruction of the clonal architecture of mutated populations in the case of multiple mutations occurring within the same amplicon

Dose Escalation of Imatinib in Chronic-Phase CML Patients

Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics Therapeutic resistance to imatinib is seen in approximately 10% to 15% of patients and can be classified as primary or secondary depending on whether an initial decline in disease levels are observed or not. 1 A major factor mediating secondary resistance is the emergence of acquired point mutations in the ABL kinase domain (KD) and BCR-ABL1.

Mechanisms of resistance to imatinib mesylate in

  1. 1. Br J Haematol. 2017 Jun;177(6):1000-1007. doi: 10.1111/bjh.14683. Epub 2017 May 3. The use of Imatinib resistance mutation analysis to direct therapy in Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia patients failing Imatinib treatment, in Patan Hospital, Nepal
  2. es therapy, putting patients at risk, and occurs in approximately 25% of patients [1]. Hence, it is important for doctors and medical students alike to understand that resistance occurs, some of the mechanisms behind resistance and how new pharmacotherapies can combat these. This review summarises the pathophysiology.
  3. imatinib resistance. Over the last 5 years, multiple studies have addressed the problem of imatinib resistance and helped to define the major elements contributing to this occurrence. Major inroads made in our under-standing of the mechanisms driving imatinib resistance have resulted in the design of novel targeted agents t

Clinical resistance to imatinib is common in patients with acute leukaemia (blast-crisis CML or Ph-positive ALL), and occurs within 3-6 months of treatment in over 70% of patients.14, 15 Once resistance develops, the disease is rapid and aggressive in most patients Purpose: Although dual src-family kinase/BCR/ABL inhibitor, dasatinib (BMS-354825), provides therapeutic advantages to imatinib-resistant cells, the mechanism of dasatinib resistance was not fully known. Experimental Design: We used TF-1 BCR/ABL cells, by introducing the BCR/ABL gene into a leukemia cell line, TF-1 and K562, and established dasatinib- (BMS-R) and imatinib-resistant (IM-R) cells Imatinib (STI571 or Gleevec) is a small-molecule inhibitor of the BCR-ABL tyrosine kinase that produces clinical remissions in chronic myeloid leukemia (CML) patients with minimal toxicity (1, 2).Imatinib is now frontline therapy for CML, but resistance is increasingly encountered As in CML, resistance to Imatinib has proved to be a significant problem in GIST as all GIST patients treated with Imatinib for advanced disease will inevitably develop progressive disease. Primary resistance was seen in 12 percent of 934 patients in the randomized European trial exploring two different doses of Imatinib and was more likely in.

Molecular correlates of imatinib resistance in

Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA . Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy Reasons for Initiating Alternative Therapy. Although the European Leukemia Net definitions for imatinib resistance to which the review refers are reasonably and widely accepted, the question of whether these should be the only accepted reasons for switching from imatinib to a second-generation kinase inhibitor or alternative therapeutic strategy remains unclear Imatinib mesylate-resistant GIST882 cell line (GIST-R) The GIST882 cell line used in this study has a gain-of-function mutation in Kit (K642E) and is sensitive to IM, resulting in apoptosis with. GIST patients resistant to imatinib/sunitinib respond to sorafenib. When GIST patients develop resistance to imatinib (Gleevec), second-line sunitinib (Sutent) has been shown to achieve a response rate of 7% and a median progression-free survival of 6.2 months. When patients progress on sunitinib, however, therapeutic options have been limited

Management of imatinib-resistant patients with chronic

  1. imatinib-resistant CML. Imatinib resistance Mutations that cause imatinib resistance are usually those that lead to a BCR-ABL protein with a functional ABL tyrosine kinase domain, but that totally abrogate or impair drug binding. On the molecular level, point mutations in BCR-ABL reduce the binding of imatinib t
  2. This is known as imatinib resistance. Resistance to imatinib seems to be caused by changes in the genes of the CML cells. Sometimes this resistance can be overcome by increasing the dose of imatinib, but some patients need to change to a different drug, such as one of the other TKIs
  3. istration of imatinib (in 2001), the first of a class of medications called tyrosine kinase inhibitors.
  4. This is a non-randomized, open-label, multicenter phase 2 study to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable GIST after prior failure or intolerability of imatinib. Patients will be enrolled into 1 of 2 cohorts based on absence (Cohort A) or presence (Cohort B) of KIT exon 13 resistance.

Imatinib is used to treat chronic myelogenous leukemia (CML), but resistance develops in all phases of this disease. The purpose of the present study was to identify the mode of resistance of newly derived imatinib-resistant (IM-R) and PD166326-resistant (PD-R) CML cells. IM-R and PD-R clones exhibited an increase in viability and a decrease in caspase activation in response to various doses. Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL In general, imatinib resistance can be subdivided into Bcr-Abl dependent and independent mechanisms. Bcr-Abl dependent mechanisms include over expression or amplification of the Bcr-Abl gene and point mutations within the Bcr-Abl kinase domain that interfere with imatinib binding. Bcr-Abl independent mechanisms include factors influencing the concentration of imatinib within the cell, for. Purpose: Gastrointestinal stromal tumors (GIST) are characterized by gain-of-function mutations in KIT / PDGFRA genes leading to a constitutive receptor activation which is well counteracted by imatinib. However, cases in which imatinib as first-line treatment has no effects are reported (primary resistance). Our purpose is to investigate alterations in downstream effectors, not reported so.

Genome-scale CRISPR-Cas9 Knockout Screening was applied to investigate novel targets in imatinib-resistant gastrointestinal stromal tumor (GIST). 20 genes and 2 miRNAs have been selected by total reads of sgRNA and sgRNA diversity, which has been further validated in imatinib-resistant GIST cells by CCK8 and qPCR analysis. Our study has finally revealed 9 genes (DBP, NR3C1, TCF12, TP53, ZNF12. Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated

Acquired resistance to imatinib in gastrointestinal

Mutations within the kinase domain of BCRABLI account for 30% to 40% of cases of imatinib resistance. Other mechanisms include BCRABLI amplification, overexpression of the SRC family of kinases, and pharmacokinetic and pharmacodynamic factors Patterns of ABL Mutation in Asian With Imatinib Resistant Chronic Myeloid Leukemia and Ph Positive Acute Lymphocytc Leuekmia Patients (AMICA) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government

Nilotinib (Tasigna; Novartis Pharmaceuticals Corporation) is a rationally designed highly potent and selective inhibitor of BCR-ABL. 7-9 In a phase 1 dose-escalation study of patients with imatinib-resistant CML, nilotinib treatment resulted in a significant proportion of patients achieving hematologic and cytogenetic responses (CyRs) in all phases of CML. 10 Results from a single-arm, open. Imatinib; Resistance; Imatinib mesylate (1-5) is a potent and selective inhibitor of the oncogenic BCR-ABL tyrosine kinase, which is deregulated in as many as 95% of chronic myeloid leukemia (CML) patients and in ∼20% of adult Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients. Despite its striking efficacy, however.

Conclusions Imatinib and nilotinib reverse MRP7-mediated paclitaxel resistance, most likely due to their inhibition of the efflux of paclitaxel via MRP7. These findings suggest that imatinib or nilotinib, in combination with other antineoplastic drugs, may be useful in the treatment of certain resistant cancers Bosutinib in CML-CP post imatinib failure • 288 pts Rx with bosutinib 500 mg/D: Imatinib resistant 200; intolerant 88 • Parameter Percent -CHR 86 -MCyR 53 -CCyR 41 -MMR if CCyR 64 -2-yr PFS 79 2-yr OS 92 • Side effects: diarrhea 9%, rash 9% Cortes. Blood 118: 4567;2012 27 Imatinib resistance related genes. After gene chip data analysis, we obtained a heat map of the differentially expressed genes of the gene chip G2810 (Additional file 1: Fig. S1), we Identified a total of 125 DEGs with imatinib resistance (Fig. 1), of which 66 were up-regulated and 59 were down-regulated.According to FC,the top 10 significantly up-regulated DEGs and down-regulated DEGs are. Patient E developed imatinib-resistant, rapidly growing implants 31 months after imatinib treatment (computed tomography scans not shown). Patients C, D, and E underwent surgery immediately at the onset of imatinib resistance, and clones 5-11 (Table 2) ⇓ were surgically removed from these three patients

Imatinib-resistant BCR-ABL1 positive cell lines. A panel of Ph+ ALL and CML cell lines was tested in [3 H]-thymidine and annexin-V/propidium iodide (PI) assays to find models for TKI-resistance studies (Figure 1).In 14/19 BCR-ABL1 positive cell lines, IC50 values for imatinib were in the range of 50 nM to 200 nM. Five cell lines showed markedly higher IC50 values: KCL-22 (800 nM), MHH-TALL1 (1. Cancer Letters-version 2 CAN-D-09-01056 p21Cip1 confers resistance to imatinib in human chronic myeloid leukemia cells Nuria Ferrandiza, Juan M. Caraballoa, Marta Albajara,b, M. Teresa Gomez-Casaresc, Carmen E. López-Jorgec, Rosa Blancoa, M. Dolores Delgadoa and Javier Leona, * a Departamento de Biología Molecular, Facultad de Medicina, Instituto de Biomedicina y Biotecnología de Cantabria. Some of imatinib-resistant patients were also resistant to nilotinib and dasatinib. Resistance was confirmed by cytogenetic and molecular studies. Sequence analysis showed that the 35-bp insertion is a normal sequence in the ABL intron 8 that is inserted between exon 8 and exon 9 ( Fig. 2 ) Imatinib, a selective inhibitor of the KIT and PDGFR kinases, is an effective agent for patients with advanced GIST, but the pivotal study of imatinib in GIST showed that 5% of patients had primary resistance to the agent and another 14% developed early resistance Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the.

In imatinib-resistant KBM-5 (KBM-5R) cells, which began to die in response to a dose between 10 and 25 μM imatinib (Additional file 1: Figure S3), the decrease in cell viability was further enhanced by co-treatments compared to treatments with either drug alone, and a synergistic loss of 65% of living cells occurred after a combination with 2. Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis In most patients with chronic myeloid leukemia (CML), the disease can be kept under control using the BCR/ABL kinase inhibitor imatinib. Nevertheless, resistance or intolerance to imatinib and other BCR/ABL inhibitors may occur during therapy. Therefore, CML research is focusing on novel targets and targeted drugs. Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays an essential. To the Editor: Acquired resistance to imatinib mesylate caused by kinase-domain mutations is common in patients with chronic myelogenous leukemia who are treated with the drug.1 Until now, such. primary imatinib resistance with higher transcript levels of the drug metabolism gene PTGS1 was confirmed in a separate data set of 68 newly diagnosed, imatinib-treated CML (P.008). In contrast, up to 11 different genes were identified in a multivariate model that optimally discriminated secondar

Cumulative mechanism of several major imatinib-resistant

• The T315I mutation appears to confer resistance to multiple targeted tyrosine kinase inhibitors. • Other mutations may be more responsive to other therapies.(1) Imatinib resistance Chronic Myeloid Leukemia (CML) Chronic Myeloid Leukemia & Imatinib Imatinib 3 alternatives CML accounts for 15%-20% of all adult leukemia are resistant to imatinib. How patients are defi ned as resistant is, therefore, important. Mechanisms of resistance The existence of patients resistant to imatinib was evident soon after the introduction of the drug into clinical practice. Initial responses were lower in patients with advanced-phase disease (ie, acceleration phase, an Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P.002). Evidence for clonal evolution and/or polyclonal secondary kinase.

The majority of patients with chronic phase chronic myeloid leukaemia (CP-CML) treated with imatinib achieves cytogenetic disease remission. Molecular monitoring for residual disease has prognostic significance: rising BCR-ABL levels may provide earliest indication that a patient has become resistant to treatment. The emergence of resistance to imatinib has dampened the enthusiasm for this. Williams and colleagues tracked the development of imatinib resistance, using a mouse model of Ph+ ALL. They engineered BCR-ABL-expressing lymphocyte progenitors that also lack the tumor suppressor protein ARF (which is deleted in more than 30% of Ph+ ALL patients, but not in CML patients, at their time of diagnosis) REVIEW ARTICLE . Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia . Roberta Bitencourt I; Ilana Zalcberg II; Iúri Drumond Louro I,III. I Master Program in Biotechnology, Universidade Federal do Espírito Santo - UFES, Vitória, ES, Brazil II Bone Marrow Transplantation Center - CEMO, Instituto Nacional do Cancer - INCA, Rio de Janeiro, RJ, Brazi Although imatinib yields antitumor activity in the vast majority of patients, it is likely that all patients eventually experience progressive disease given enough time. In recent years, major progress has been made in the elucidation of mechanisms conferring resistance to imatinib that result in progressive disease Imatinib (400 mg/day) is the only clinically approved front-line TKI therapy for CML. Patients should be monitored for imatinib resistance based on National Comprehensive Cancer Network (NCCN) guidelines

A therapeutically targetable mechanism of BCR-ABLPPT - Resistance to Imatinib in Chronic MyelogenousThe structure of the leukemia drug imatinib bound to human

Out of 18 mutation types, 16 had been previously associated with Imatinib resistance. The mutations that have a strong resistance to Imatinib, i.e., T315I, E255V, Y253H, L248V, E279K and G250E, were documented in 13 patients Imatinib non‐responder CML patients are classified as patients with primary resistance (n = 26) and patients with secondary resistance (n = 6). The patients who failed in IM has switched to second‐generation TKI as dasatinib (n = 11) or nilotinib (n = 21) Abstract. Introduction: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown. Methods: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established.EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models

Imatinib in Chronic Myeloid Leukemia: an Overvie

clinically common imatinib-resistant muta-tion M351T (which accounts for 15 to 20% of CML resistance cases) appeared healthy with no evidence of weight loss, lethargy, or ruf-fled fur and showed greater than one log lower levels of bioluminescent activity after 2 weeks of therapy. Consistent with our in vitr Common Questions and Answers about Imatinib resistant gleevec Eithne01, The treatment of chronic myeloid leukemia (CML) has changed significantly since the late 1990s, with the development and subsequent approval by the Food and Drug Administration of imatinib (in 2001), the first of a class of medications called tyrosine kinase inhibitors. Dasatinib Overcomes Imatinib Resistance for Chronic Myeloid Leukemia. Dec. 12, 2005 (Atlanta) — Dasatinib, an investigational oral drug, produces positive results in patients with chronic. As mentioned in the Introduction, the manifestation of imatinib resistance has driven the development of second generation (2G) TKIs with superior activity compared to imatinib in both facilitating molecular remission and preventing disease progression (16, 19, 81). A natural progression of the findings with interferon-imatinib combination. Bcr-Abl-independent signaling pathways are known to be involved in imatinib resistance in some patients with chronic myelogenous leukemia (CML). In this study, to find new targets for imatinib-resistant CML displaying loss of Bcr-Abl kinase target dependence, we isolated imatinib-resistant variants, K562/R1, K562/R2, and K562/R3, which showed profound declines of Bcr-Abl levels and its.

Seeking the causes and solutions to imatinib-resistance in

BCR-ABL Tyrosine Kinase inhibitor is an ideal pharmacological target for Chronic Myeloid Leukemia (CML). After the effective use of Imatinib as a therapeutic agent for Chronic Myeloid Leukemia, resistance has been observed in much patience with the treatment of Imatinib. The main objective of this study is to develop some new novel BCR-ABL Tyrosine Kinase [ The multitargeted tyrosine-kinase inhibitor (MKI) imatinib mesylate (Glivec, Novartis, Basel, Switzerland) revolutionised the treatment for advanced disease. Although most patients benefit from imatinib, many subsequently develop acquired resistance.3 In patients developing resistance to imatinib, other MKIs provide clinical benefit Imatinib resistance was induced in these as described. (A) Morphological identification of apoptotic cells: cell lines that were initially imatinib-sensitive (LAMA84, K562, and Cells were collected, washed, and stained with acridine orange, KCL22) by continuous culture exposure up to 1 mM. All according to the method of Saydam et al. (2003) Abstract Although imatinib (IM) has been demonstrated to be an efficient treatment in chronic myeloid leukemia (CML), some patients still experience IM resistance and disease relapse. Through in vi..

Defining and Managing Imatinib Resistance Hematology

Most common ARs & most common grade 3/4 ARs (imatinib-resistant or ‑intolerant GIST): The most common ARs reported in ≥20% of patients with GIST and more commonly with SUTENT than placebo (all grades, vs placebo) were diarrhea (40% vs 27%), anorexia (33% vs 29%), skin discoloration (30% vs 23%), mucositis/stomatitis (29% vs 18%), asthenia. The BCR/ABL tyrosine kinase inhibitor, imatinib, has shown substantial effects in blast crises of chronic myelogenous leukemia. However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem for patients being treated with imatinib

Mechanisms of Resistance to Imatinib and Second-Generation

Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumor An imatinib-resistant cell line produced by culturing the cells in suboptimal concentrations of imatinib 8 showed a 4-fold increase in expression of the BCR-ABL protein. The BCR-ABL in these cells was still sensitive to imatinib, but, because of the increased protein levels, a higher intracellular imatinib concentration was required to induce. The aim of this study was to investigate the associations between secondary mutations of c-KIT/PDGFRα and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRα (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing

Resistance to Tyrosine Kinase Inhibitors in

Although Imatinib and other tyrosine kinase inhibitors (TKIs) have excellent results, the appearance of resistance is a problem in chronic myeloid leukaemia (CML). PI3K/AKT/mTOR pathway is activated by BCR-ABL playing a crucial rule in CML. This study aimed to evaluate the therapeutic potential of Everolimus, in CML models sensitive and resistant to Imatinib Imatinib resistance is most often caused by BCR-ABL‐dependent mechanisms, including point mutations in the functional kinase domain of BCR-ABL (5, 6) and amplification of the BCR-ABL fusion gene. Point mutations in BCR-ABL reduce the binding of imatinib to the protein by either a direct or an indirect mechanism Despite the success of imatinib and other tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains largely incurable, and a number of CML patients die due to Abl mutation-related drug resistance and blast crisis. The aim of this study was to evaluate proliferation inhibition and apoptosis induction by down-regulating PPP2R5C gene expression in the imatinib-sensitive and. Imatinib is able to bind the inactive conformation of BCR/ABL, preventing adenosine triphosphate from entering its binding pocket. 4 A variable portion of patients experience resistance to imatinib therapy, depending on the phase and type of disease. 5 Resistance can arise from different mechanisms, such as BCR/ABL amplification 6 and low.

File:Mechanism imatinibSecond generation inhibitors of BCR-ABL for the treatment

Exovesicular-Shh confers Imatinib resistance by

In conclusion, platinum resistance and imatinib resistance in metastatic colorectal cancer were modeled using the gel-free 3D cultured tumoroid with increased stem cell properties. The 3D tumoroid system is useful and easily accessible for drug assessment, including chemosensitivity and chemoresistance All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation The in vitro analysis using K294RGG mutant BCR-ABL-expressing 32D cells revealed that K294RGG mutation was imatinib resistant but dasatinib sensitive. Consistent with the in vitro data, the clone with K294RGG mutation was eliminated by the dasatinib treatment in this patient. During the imatinib treatment, several mutant clones emerged and. Sensitive PCR-based testing showed that 32 of 52 (62%) imatinib-resistant CML patients in chronic phase and 8 of 38 (21%) in accelerated or blast crisis expressed varying levels of the alternatively spliced BCR-ABL mRNA. A three-dimensional structural model of the 35INS ABL kinase domain complexed with imatinib was built using homology modeling.

Incidence of imatinib resistance in chronic myeloid

Taken together, potential mechanisms, how decreased expression of miR-142-5p and miR-365a-3p might contribute to development of imatinib resistance in CML patients could be suggested based on our findings and on literature data. However, it must be taken into account that these interaction data were generated in an in vitro setup Furthermore, Imatinib resistant K562G cells and patients with Imatinib resistance had much lower expression level of USP15. Depletion of USP15 increased, while overexpression of USP15 reduced the resistance of CML cells to Imatinib, suggesting that USP15 may function as a tumor suppressor in CML and involve in Imatinib resistance

A randomized, double-blind, placebo-controlled study did not find evidence to support the hypothesis that imatinib shortens time needed on oxygen support for patients with severe COVID-19, according to the results of a study published in Lancet Respiratory Medicine.. Patients with COVID-19 requiring supplemental oxygen at 13 large teaching hospitals in the Netherlands between March 31, 2020. Median progression-free survival (PFS) was 6.0 months, which compares well with results seen with established drugs in imatinib-resistant disease in Phase 3 trials. In terms of safety, the most common cabozantinib-related grade > 3 adverse events were diarrhea, hand-foot syndrome, fatigue, hypertension, weight loss and oral mucositis, with 33. Eighteen imatinib-resistant BCR-ABL mutations were detected among 25 of these patients (24 imatinib-resistant and 1 imatinib-intolerant) throughout the BCR-ABL kinase domain. The T315I mutation, which was found in 6 patients, was the most common. Eleven patients (34%). Resistance to imatinib may be primary or secondary. Primary resistance is defined as continuous growth or growth within 6 months of therapy, and occurs in 15-20% of patients with advanced GIST [ 109 ] and occurs frequently in patients with wild-type (WT) GIST or KIT exon 9 mutations or D842V mutation in PDGFRA exon 18 [ 110 ] Unfortunately, some patients, especially in the progressive phase of the disease, show no response or relapse due to resistance. The major mechanism of imatinib resistance is a Bcr-Abl kinase domain mutation and the existence of leukemia stem cells . Allo-HSCT is recommended as an initial treatment for younger patients with HLA-matched donors.