scholarly journals Development of the Rat Model of Lapatinib-Induced Diarrhoea

Scientifica ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Joanne M. Bowen
Keyword(s):  
Adverse Effect ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Rat Model ◽  
Kinase Inhibitors ◽  
Clinical Observation ◽  
Clinically Significant ◽  
Egfr Tki

Targeted therapy of cancer is often associated with clinically significant diarrhoea; however, the mechanisms underpinning this adverse effect are currently unknown. Diarrhoea following treatment with tyrosine kinase inhibitors (TKIs) of EGFR is particularly troublesome. Until recently, understanding of EGFR TKI-induced diarrhoea has been limited to clinical observation. However, our group has recently developed the first rat model of EGFR TKI-induced diarrhoea. This paper reviews the published and unpublished findings.

EGFR tyrosine kinase inhibitors in non-small cell lung cancer: treatment paradigm, current evidence, and challenges

2020 ◽  
pp. 030089162096813
Author(s):  
Arafat Tfayli ◽  
Razan Mohty
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with EGFR-mutated non-small cell lung cancer (NSCLC) has been shown to have superior outcomes when compared to chemotherapy. First-generation EGFR TKI, including gefitinib and erlotinib, and second-generation EGFR TKI, including afatinib and dacomitinib, proved to be effective in patients with NSCLC harboring EGFR-sensitizing mutation. Later, resistance mutations were identified. Consequently, osimertinib, a third-generation EGFR TKI, was studied and demonstrated activity against EGFR-sensitizing and resistant mutations. Osimertinib moved recently to the first-line setting with the positive results of the FLAURA (AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer) trial. The use of these drugs is limited by their cost and availability mainly in middle- to low-income countries.

scholarly journals Radionuclide monitoring of targeted therapy of iodine-negative differentiated thyroid cancer

2021 ◽  
Vol 29 (1) ◽  
pp. 141-155
Author(s):  
O. I. Solodiannykova ◽  
Ya. V. Kmetyuk ◽  
V. V. Danylenko ◽  
H. H. Sukach
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Whole Body ◽  
Pet Ct ◽  
18F Fdg ◽  
99Mtc Mibi

Background. Current management of treating iodine-negative metastases of differentiated thyroid cancer has its features. In recent years, tyrosine kinase inhibitors (sorafenib, sunitinib) have been registered and indicated to treat refractory forms of differentiated thyroid cancer in Ukraine. However, there were only few studies dealing with cytologic aspects of predicting radioiodine resistance of papillary thyroid cancer, development of radionuclide monitoring and diagnostic algorithm to detect relapses and metastases in patients with iodine-negative forms of differentiated thyroid cancer. At the same time, scientific and clinical aspects of treatment of radioiodineresistant differentiated thyroid cancer in Ukrainian oncology and radiology are barely studied. Thus, the status of treatment and post-therapeutic monitoring of patients with iodine-negative forms of differentiated thyroid cancer, still remains insufficiently studied and requires further scientific and clinical development. Purpose – develop a technique of treatment of iodine-negative metastases of differentiated thyroid cancer. Materials and methods. Thirty-eight patients with iodine-negative metastases of differentiated thyroid cancer were provided with treatment, where in 10 patients the efficiency of treatment was assessed by means of whole body scintigraphy with 99mTc-MIBI, in 10 patients – with 99mTcDMCA. In 10 patients the short-term results of treatment with tyrosine kinase inhibitors were evaluated by PET with 18F-FDG. Eight patients represented a group where the bones were affected and treatment was provided by means of radionuclide or external-beam radiotherapy. The average age of patients varied from 43 to 76, the median was 57.8 + 3.9; out of those: 24 women, 14 men. Pathohistologically, papillary cancer was diagnosed in 31, follicular – in 5, papillary-follicular – in 2. The studies were performed by means of the two-detector gamma camera manufactured by Mediso (Hungary) and the single-photon emission computed tomography (SPECT) E. CAM 180, Siemens (Germany). PET/CT were performed on the Biograph-64-TruePoint-Siemens combined tomograph (Germany), according to the guidelines of the European Association of Nuclear Physicians. Results. Prior to initiating therapy, 10 patients with differentiated thyroid cancer underwent whole body scintigraphy with 99mTc-MIBI and re-examination in three months in order to assess treatment success. After diagnostic examination, the patient was prescribed targeted therapy with Nexavar according to the treatment protocol. Regression of the focus in the lungs was achieved within 70 %. Further monitoring of antitumor treatment success was performed by means of whole body scintigraphy with 99mTc-MIBI. Ten patients, who had PET/CT with 18F-FDG made before treatment, also underwent targeted therapy by means of Nexavar. Diagnostic scanning with 18F-FDG after therapy revealed decreased functional activity of the lesion in the neck, however no decrease in the dimensions of the lesion was observed. Conclusions. Treatment of iodine-negative metastases of differentiated thyroid cancer by means of tyrosine kinase inhibitors was accompanied by a decreasing number of metastatic foci and reducing level of their functional activity. The studies have confirmed the possibility of applying techniques with non-iodine RP (99mTc-MIBI, 99mTc-DMCA) to assess the effectiveness of treatment of iodine-negative metastases of differentiated thyroid cancer . PET/CT with 18F-FDG is a highly informative technique for assessing the effect of tyrosine kinase inhibitors on the functional activity of metastatic foci according to metabolic scans in treatment of iodine-negative metastases of differentiated thyroid cancer. If there are no positive changes after 3–4 courses, external-beam radiotherapy with total radiation dose of 30–50 Gy is indicated, which is capable of reducing the volume of metastatic foci as well as their metabolic activity. The social and economic significance of the obtained findings have made it possible to improve the overall and recurrence-free survival rates in the working population of patients with differentiated thyroid cancer and reduce the cost of following-up patients with iodine-negative forms of differentiated thyroid cancer.

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

Mutation Mediated Resistance to the Tyrosine Kinase Inhibitors Imatinib, Dasatinib & Nilotinib in Philadelphia Positive Leukaemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4245-4245 ◽  
Author(s):  
Lisa M O’ Connor ◽  
Stephen Langabeer ◽  
Shaun R. McCann ◽  
Eibhlin Conneally
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Molecular Mechanisms ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Kinase Domain ◽  
Patient Specific ◽  
Abl Kinase ◽  
Clinically Significant

Abstract The Philadelphia chromosome is formed as a result of a reciprocal translocation between chromosomes 9 and 22 and results in the formation of the hybrid oncoprotein BCR-ABL. It is observed in over 95% of Chronic Myeloid Leukaemia (CML) and approximately 30% of adult Acute Lymphoblastic Leukaemia (ALL) cases. Imatinib Mesylate (IM), a tyrosine kinase inhibitor that specifically binds BCR-ABL in its inactive conformation has revolutionized therapy for CML and Ph+ ALL. However, resistance develops in a significant proportion of patients and is predominantly mediated by single base-pair substitutions within the BCR-ABL kinase domain leading to changes in the amino acid composition that inhibit IM binding whilst retaining BCR-ABL phosphorylation capacity. Second generation tyrosine kinase inhibitors such as Dasatinib and Nilotinib retain activity in IM-resistant patients due to less stringent binding requirements and represent viable alternatives for IM-resistant patients with a suitable molecular profile. In this study, we undertook to examine the molecular mechanisms underlying IM resistance. A cohort of 40 patients with either primary or acquired resistance or intolerance to IM was identified by persistent high or increasing levels of BCR-ABL transcripts determined by real-time quantitative PCR. An allele-specific PCR screen was used to sensitively detect the clinically significant T315I mutation, which renders patients insensitive to currently available tyrosine kinase inhibitors: five (12.5%) IM resistant/intolerant patients were T315I positive. To further elucidate the molecular mechanisms of mutation induced resistance, the BCR-ABL kinase domain was screened for the presence of a mutation using a sensitive denaturing high performance liquid chromatography (dHPLC) approach. Samples showing evidence of mutation were examined by direct sequencing to identify the mutation(s) present. Kinase domain mutations have been identified in 20 of the 40 (50%) patients examined to date and these include p-loop mutations (M244V, G250E, Q252H), IM-binding domain mutations (T315I), catalytic domain mutations (M351T), an activation-loop mutation (L387M). Three previously unreported mutations were identified in patients with indications of IM resistance (T267A, E275Q) and Nilotinib resistance (L273M). The L273 residue lies adjacent to a region of the BCR-ABL kinase domain bound by Nilotinib. Three patients were found to harbour mutations at two distinct kinase domain residues while one patient harboured mutations at three distinct residues, supporting the theory that patients who develop mutation-mediated resistance to one kinase inhibitor may become resistant to subsequent inhibitors by a similar mechanism. The identification of clinically significant mutations facilitates selection of alternative approaches to therapy such as dose escalation of IM, second generation tyrosine kinase inhibitors or allogeneic stem cell transplant, if eligible, at an early stage in a patient’s disease, tailoring patient specific approaches to therapy.

scholarly journals Letter to the Editor About the Adverse Effect of Combined Tyrosine Kinase Inhibitors

2020 ◽  
Vol 15 (11) ◽  
pp. e181-e182
Author(s):  
Zihui Li ◽  
Jie Deng ◽  
Fei Yan ◽  
Yanling Ma ◽  
Jianhai Sun
Keyword(s):  
Adverse Effect ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Letter To The Editor

scholarly journals Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer

2020 ◽  
Author(s):  
Kazumi Sano ◽  
Kazuhiko Nakadate ◽  
Kazuhiko Hanada
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Skin Disorder ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Tki

Abstract Background While epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors(TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. Objective This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Geotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline. Methods First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder. Results Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically. Discussion These results suggest that minocycline applied both locally and orally prevents and repairs afatinib-induced skin disorders. Histological examination of skin elucidated the mechanism of the occurrence of the EGFR-TKI-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

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