Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

Advances in MET tyrosine kinase inhibitors in gastric cancer

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer

The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.

Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients Harboring Different Types of EGFR Mutations:A Retrospective Analysis

With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung cancer（NSCLC） patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations（co-occurrence of two or more different mutations）, has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate（DCR） was 93.7% with two patients（0.2%） achieving complete response（CR）, the median progression free survival（PFS） was 13.0 months（95% confidence interval [CI], 11.6–14.4 months）, and the median overall survival（OS） was 55.0 months（95% CI, 26.3–83.7 months）. Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858 R mutation（P〈0.001）. Patients with classic mutations（del-19 and/or L858 R mutations） demonstrated longer PFS（P〈0.001） and OS（P=0.017） than those with uncommon mutations（single rare and/or complex mutations）. Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS（hazard ratio [HR]=0.308, 95% CI, 0.191–0.494, P〈0.001） and OS（HR=0.221, 95% CI, 0.101–0.480, P〈0.001）. The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations（especially for the patients with single rare mutations） are needed to determine a better precision treatment.

Tyrosine Kinase Inhibitors against Cancer: Their Safety in 216 Moroccan Patients

Tyrosine kinase inhibitors (TKIs) have become a prominent option in the therapeutic arsenal of several cancers. The safety of these drugs has shown various toxicities with varying frequency and severity between different agents. The aim of this study is to describe the safety profile of different classes of TKI used in various solid tumors. It is a retrospectively descriptive study conducted in the Department of Medical Oncology at Hassan II University Hospital of Fez, Morocco, over a period of 6 years from April 2013 until April 2019. It included 216 patients who received one or more TKI for different indications in solid tumors. The average age in our series was 61.4 years with a sex ratio F/M of 1.07. Among the most used TKIs in our department according to their availability: Imatinib (32%) and sunitinib (32%). All patients received one or more tyrosine kinase inhibitors according to the indication. Kidney cancer was the most common malignancy (36%), followed by gastrointestinal stromal tumors (33%). The median duration of treatment was 15 months with extremes of 1 month and 102 months. The main side effects were: Cutaneous in 43% of patients. Digestive toxicity occurred in 36% of cases. Hematotoxicity was reported in 33% of cases. The safety profile of TKIs used in our study was comparable to their global tolerance reported in literature. More studies are needed to investigate the relationship between their toxicity and their efficacy in Moroccan population.

Immediate Versus Delayed Treatment with EGFR Tyrosine Kinase Inhibitors after First-line Therapy in Advanced Non-small-cell Lung Cancer

Objective： To analyze the outcomes of patients who received TKI immediately after the first-line without progression as maintenance treatment （immediate group） vs. those received delayed treatment upon disease progression as second-line therapy （delayed group）. Methods： The study included 159 no-small-cell lung cancer （NSCLC） patients who received gefitinib or erlotinib as maintenance treatment in the immediate group （85 patients） or as second-line therapy in the delayed group （74 patients）. The primary end point was progression-free survival （PFS）. EGFR mutation status was detected using denaturing high-performance liquid chromatography （DHPLC）. Results： PFS was 17.3 and 16.4 months in the immediate and delayed groups, respectively （hazard ratio [HR], 0.99; 95% Confidence Interval [CI]： 0.69-1.42; P=0.947）. In a subgroup analysis that included only patients with EGFR mutation, however, PFS was significantly longer in the immediate group than in the delayed group （HR, 0.48; 95% CI： 0.27-0.85; P=0.012）. In patients with wild type EGFR, the risk for disease progression was comparable between the two groups （HR, 1.23; 95% CI： 0.61-2.51; P=0.564）. No significant difference was demonstrated between the immediate and delayed group in terms of the overall survival （OS） （26.1 months vs. 21.6 months, respectively; HR=0.53; 95% CI： 0.27 to 1.06; P=0.072）. There was also no difference in the incidence of adverse events between the two groups. Conclusions： EGFR TKI maintenance improves PFS in patients with EGFR mutation. Prospectively designed clinical studies that compare TKI immediate vs. delayed treatment after first-line chemotherapy upon disease progression are needed.

Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment:A Case report

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors

Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not understood.The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.Methods:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients.We evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC patients.Based on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted.Additionally,in vivo genetic and pharmacological gain-and loss-of-function experiments were performed.Results:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival.Mechanistically,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling.IGFBP-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase pathway.Consequently,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.Conclusions:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic TKIs.Antiangiogenic TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 pathway.These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

Allogeneic hematopoietic stem cell transplantation for the treatment of chronic myeloid leukemia in the era of tyrosine kinase inhibitors

The approval of imatinib in 2001 has changed the landscape of CML management.^-3 With its excellent efficacy in the International Interferon and STI571 （IRIS）, Randomized Study of imatinib has become the standard of care for newly diagnosed patients. This change challenges the previous role of allogeneic hematopoietic stem cell transplantation （allo-HSCT） in CML treatment. However,

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors(BTKis)in the treatment of elderly patients with DLBCL.CASE SUMMARY The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with BTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients,thus providing a new treatment strategy.

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

The tyrosine kinase inhibitors （TKI） of the epidermal growth factor receptor （EGFR） are becoming the first line of therapy for advanced non-small cell lung cancer （NSCLC）. Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 （osimertinib; Tagrisso） is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

miR-30b and miR-30c expression predicted response to tyrosine kinase inhibitors as first line treatment in non-small cell lung cancer

Background Aberrantly expressed microRNAs are a hallmark of cancer,and microRNA expression profiling is associated with tumor progression and response to chemotherapy,suggesting their potential application as prognostic and predictive biomarkers.The role of microRNAs in lung cancer remains elusive.It has been recently reported that epidermal growth factor receptor （EGFR） and hepatocyte growth factor receptor （MET） tyrosine kinase can regulate expression of specific microRNAs including miR-30b,miR-30c,miR-221,miR-222,miR-103 and miR-203,and induce tumorigenesis and gefitinib resistance in lung cancers.We intend to study the role of miR-30b and miR-30c expression in predicting response to tyrosine kinase inhibitors （TKIs） in non-small cell lung cancer （NSCLC）.Methods We have therefore retrospectively examined expression of miR-30b miR-30c in 41 formalin fixed paraffin embedded tissue samples from NSCLC patients when TKIs were used as first line therapy.Results We found a significant correlation between expression of miR-30b and miR-30c.Furthermore,miR-30b and miR-30c expression correlated with short-term response.Kaplan-Meier analysis further revealed that the expression of miR-30b and miR-30c predicted progression free survival and the overall survival rate in the examined cohort.Conclusion Our study identified miR-30b and miR-30c as useful prognostic predictors in NSCLC patients who underwent first line treatment with TKIs.

Mechanisms of acquired resistance to tyrosine kinase inhibitors

In recent years,structural and functional studies reveal that tyrosine kinases(TKs)act as the essential components of signal transduction pathways that regulate cancer cell proliferation,apoptosis and angiogenesis,and therefore become potential targets for anticancer therapy.Most of TK inhibitors(TKIs)are small molecular and hydrophobic compounds,thus they can rapidly reach their specific intracellular targets and inhibit the activation of the related TKs.Unfortunately,accompanied with patients who gain great benefit of TKIs therapy,increasing evidences of acquired resistance to these agents have been documented.The unveiling point mutations within the kinase domain,gene amplification or overexpression,or modification of signaling pathway have been implicated in drug resistance.Additionally,overexpression of ABC transporters is likely to set stage for resistant development.In this review,we focus on the discussion of the molecular mechanisms of acquired resistance to TKIs therapy.The mechanistic understanding may help to put forward new hypotheses on drug development and design better therapies to overcome TKIs resistance.

Effect of a novel tyrosine kinase inhibitor nintedanib on bFGF and VEGF concentrations in a rabbit retinal vein occlusion model

AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.METHODS:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a control.Intracameral samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after treatment.Enzyme-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous humor.RESULTS:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both eyes.In the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third day.After nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several weeks.CONCLUSION:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.

Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

Mutated or rearranged driver kinases in non-small cell lung cancer(NSCLC)cells are clinically amenable to treatment with tyrosine kinase inhibitors(TKIs)resulting in prolonged survival and significant benefit compared to cytotoxic chemotherapy.The most frequent genomic alterations are observed for epidermal growth factor receptor and anaplastic lymphoma kinase,which can be blocked by a range of specific TKIs in sequence.In clinics,resistance to TKIs emerges after approximately one year and comprises secondary mutations of the kinases(on-target)or alternative pathways circumventing the original kinase(off-target)alterations.A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer(SCLC)in up to 14%of cases,which,in general,is accompanied by resistance to the original TKIs.SCLC transformed tumors may be treated with the classical platinum/etoposide regimen but thus far there are no definitive guidelines.Four transformed pleural SCLC lines in our lab indicate the presence of a gradual NSCLC-SCLC shift with overlapping drug sensitivities.In conclusion,the treatment of NSCLC-SCLC transformed cancer cells would need a better chemosensitivity assessment using functional genomics to guide further therapy.

Role of spleen tyrosine kinase in liver diseases

Spleen tyrosine kinase (SYK),a non-receptor tyrosine kinase,is expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses.SYK mediate diverse cellular responses via an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways,ITAMs-independent and ITAMs-semidependent signalling pathways.In liver,SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells) and found to be positively correlated with the disease severity.The implication of SYK pathway has been reported in different liver diseases including liver fibrosis,viral hepatitis,alcoholic liver disease,non-alcoholic steatohepatitis and hepatocellular carcinoma.Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target.This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.

Predictive indicators of successful tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia

Clinical trials have demonstrated that some patients with chronic myeloid leukemia(CML)treated for several years with tyrosine kinase inhibitors(TKIs)who have maintained a molecular response can successfully discontinue treatment without relapsing.Treatment free remission(TFR)can be reached by approximately 50%of patients who discontinue.Despite having similar levels of deep molecular response and an identical duration of treatment,the factors that influence the successful discontinuation of CML patients remain to be determined.In this review we will explore the factors identified to date that can help predict whether a patient will successfully achieve TFR.We will also discuss the need for the identification of predictive biomarkers associated with a high probability of achieving TFR for the future personalized identification of patients who are suitable for the discontinuation of TKI treatment.

Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization

AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were used.Corneal NV was induced by NaOH in the left eyes of each rat.Following the establishment of alkali burn,the animals were randomized into five groups according to topical treatment.Group 1(n=6)received 0.9%NaCl,Group 2(n=6)received dimethyl sulfoxide,Group 3(n=6)received regorafenib 1 mg/mL,Group 4(n=6)received bevacizumab 5 mg/mL and Group 5(n=6)received 0.1%dexamethasone phosphate.On the 7d,the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging analysis.The corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by immunostaining.RESULTS:A statistically significant difference in the percent area of corneal NV was found among the groups(P【0.001).Although the Group 5 had the smallest percent area of corneal NV,there was no difference among Groups 3,4 and 5(P】0.005).There was a statistically significant difference among the groups in apoptotic cell density(P=0.002).The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups(P【0.05).The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3,4 and 5 thanin Groups 1 and 2.CONCLUSION:Topical administration of regorafenib 1mg/mL is partly effective for preventing alkali-induced corneal NV in rats.

ABNORMAL PROTEIN TYROSINE KINASES ASSOCIATED WITH HUMAN HAEMATOLOGICAL MALIGNANCIES

Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoproteins and their causative role in some leukemias and lymphomas. Results: Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiations. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) plays an etiologic role in several clonal hematopoietic malignancies. For example, the PTK product of the BCR-ABL fusion gene resulting from the t (9; 22) translocation exhibits several fold higher tyrosine kinase activity than the product of the ABL gene. Evidence suggests that the BCR-ABL oncoprotein alone is sufficient to case chronic myelogenous leukemia (CML) and other Ph positive acute leukemia. PTK over-activity resulting from chromosomal translocations creating TEL-ABL, TEL-JAK2 and TEL-PDGFRβ fusion proteins plays an important role in the pathogenesis of other types of leukemia. Another example occurs in anaplastic large cell lymphoma (ALCL). Experimental and clinical evidences indicate that translocations involving ALK gene on chromosome 2p23, most commonly resulting in an NPM-ALK fusion oncogene, result in constitutive activation of ALK and cause ALCL. This group of lymphomas is now named ALK positive lymphoma or ALKoma. Conclusion: Genetic lesions creating aberrant fusion proteins that result in excessive PTK activity are increasingly being recognized as central to the pathogenesis of hemotopoietic malignancies. These chimeric PTK molecules represent attractive disease-specific targets against which new classes therapeutic agents are being developed.