Application Of Tyrosine Kinase Inhibitors Research Articles

Allogeneic stem cell transplantation is still a highly curative therapy in adults with philadelphia chromosome-positive acute lymphoblastic leukaemia.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.

Management of chronic myelogenous leukemia with COVID-19 and hepatitis B.

The application of immunosuppressive agents and targeted drugs has opened a novel approach for the treatment of hematological tumors, and the application of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia is one of the landmark breakthroughs that has considerably improved the prognosis of CML patients. However, with the extensive use of TKI, the co-infection of CML patients has become increasingly apparent, especially regarding infectious diseases such as hepatitis B and COVID-19. The underlying mechanism may be related to the inhibition of the immune function by TKI. Poor management, including disease progression due to the infectious disease or TKI dose reduction or discontinuation, may lead to adverse clinical outcomes and can even be life-threatening. Therefore, this review principally provides an overview of the pathogenesis and standardized management principles of CML patients with comorbid COVID-19 or hepatitis B in order to improve clinicians' awareness of the risks so as to more effectively diagnose and treat CML and improve the survival rate and quality of life of patients. In the past two decades, owing to the advent of imatinib, chronic myeloid leukemia (CML) has transformed into a chronic controllable disease, and even treatment-free remission can be anticipated. Earlier studies have indicated that tyrosine kinase inhibitor (TKI) exerts a peculiar inhibitory effect on the body's immune function. Therefore, with the widespread application of TKI, more and more attention has been paid to the comorbidity of infectious diseases in CML patients, especially in patients with progressive disease or non-remission. Despite some studies revealing that the proportion and severity of SARS-CoV-2 infection in CML patients receiving TKI treatment are lower than in patients with other hematological malignancies, CML patients with stable disease are still recommended to be vaccinated against SARS-CoV-2, while TKI may or may not be discontinued. Meanwhile, the management of CML patients during the epidemic of coronavirus disease 2019 (COVID-19) still necessitates further discussion. This article also provides an overview of TKI-related hepatitis B reactivation. If not managed, patients may face adverse consequences such as hepatitis B reactivation-related hepatitis, liver failure, and progression of CML after forced withdrawal of medication. Therefore, this review aimed to comprehensively describe the management of CML patients with comorbid COVID-19, the pathogenesis of hepatitis B reactivation, the indicated population for prophylactic antiviral therapy, the time of antiviral drug discontinuation, and drug selection.

ADC vs HP dual-antibody for HER2-positive advanced breast cancer after failed to TKI.

e13036 Background: The application of tyrosine kinase inhibitor (TKI) is higher than that of antibody-drug conjugate (ADC) in the second-line anti-HER2 targeted therapy of patients with advanced breast cancer in China. The purpose of this study is to explore the efficacy and safety of the new generation anti-HER2 ADC, the previous generation ADC(T-DM1) and HP dual-antibody (trastuzumab + pertuzumab) in patients with HER2 positive advanced breast cancer who failed TKI therapy. Methods: This is a retrospective, nonrandomized, controlled study to compare the regimen of the new generation ADC, HP dual-antibody and T-DM1 for patients who failed TKI treatment. The primary end point was progression-free survival (PFS). The secondary end points included the overall response rate (ORR), the clinical benefit rate (CBR) and the safety. Results: A total of 213 patients were enrolled from January 2013 to June 2022. All patients were from the department of oncology, the fifth medical center of Chinese PLA General Hospital. The median age of all patients was 47y. Among these patients,73 cases were in the new generation ADC group (including DS8201 30 cases, MRG002 24 cases, ARX788 10 cases and RC48 9 cases), 71 cases were in T-DM1 group and 69 cases were in HP group (combination chemotherapy including taxane, vinorelbine, gemcitabine and capecitabine). The median PFS of the patients in the new generation ADC group , HP group and T-DM1 group was 7.0m, 6.6m, 4.0m respectively. The difference between the new generation ADC group and T-DM1 group was significant (HR=0.44,95%CI 0.30-0.66, P&lt;0.0001), which between HP group and T-DM1 group was also significant (HR=0.50,95%CI 0.34-0.74, P&lt;0.0001), meanwhile, which between the new generation ADC group and HP group was not significantly (HR=0.88, 95%CI 0.58-1.32, P=0.527)(Figure 1). The ORR in three groups was 54.8%, 27.5%, 22.5% respectively, and the new generation ADC group was significantly higher than the other two groups (P&lt;0.0001). The CBR in three groups was 65.8%, 62.3%, 47.9% respectively. The difference between the new generation ADC group and HP group was not significantly (P=0.67), and both were significantly higher than T-DM1 group (P=0.03). The most common grade 3 or 4 adverse event in the new generation ADC group was neutropenia (20.5%) and which in T-DM1 group was thrombocytopenia (28.1%). The incidence of interstitial lung disease in the two groups was 5.4% and 1.4% respectively. No grade 5 adverse event occurred. Conclusions: In our study, the new generation ADC significantly improved PFS and ORR compared with that for T-DM1 with manageable toxicity, so it can be considered an optimized subsequent treatment for HER2 positive advanced breast cancer after TKI failure. In addition, there was no significant difference in PFS and CBR between HP and the new generation ADC, thus HP dual-antibody regimen is also an optional treatment for patients who never used pertuzumab.

Recent Advances in Boosting EGFR Tyrosine Kinase Inhibitors-Based Cancer Therapy.

Epidermal growth factor receptor (EGFR) plays a key role in signal transduction pathways associated with cell proliferation, growth, and survival. Its overexpression and aberrant activation in malignancy correlate with poor prognosis and short survival. Targeting inhibition of EGFR by small-molecular tyrosine kinase inhibitors (TKIs) is emerging as an important treatment model besides of chemotherapy, greatly reshaping the landscape of cancer therapy. However, they are still challenged by the off-targeted toxicity, relatively limited cancer types, and drug resistance after long-term therapy. In this review, we summarize the recent progress of oral, pulmonary, and injectable drug delivery systems for enhanced and targeting TKI delivery to tumors and reduced side effects. Importantly, EGFR-TKI-based combination therapies not only greatly broaden the applicable cancer types of EGFR-TKI but also significantly improve the anticancer effect. The mechanisms of TKI resistance are summarized, and current strategies to overcome TKI resistance as well as the application of TKI in reversing chemotherapy resistance are discussed. Finally, we provide a perspective on the future research of EGFR-TKI-based cancer therapy.

Alterations in cellular metabolisms after TKI therapy for Philadelphia chromosome-positive leukemia in children: A review.

Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.

Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, disease recurrence after TKI discontinuation and clinical resistance mainly due to BCR-ABL mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC50 value of 2.7 nM and Dmax of 91.2% against BCR-ABL and has an IC50 value of 12 nM in BCR-ABL + K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust BCR-ABL degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded BCR-ABL and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of BCR-ABL, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting BCR-ABL and novel potential therapeutic agents for CML treatment.

The HSP90 inhibitor KW-2478 depletes the malignancy of BCR/ABL and overcomes the imatinib-resistance caused by BCR/ABL amplification

BackgroundWith the widespread clinical application of tyrosine kinase inhibitors (TKIs), an increasing number of chronic myeloid leukaemia (CML) patients have developed resistance or intolerance to TKIs. BCR/ABL is the oncoprotein of CML. HSP90 is an essential chaperone of BCR/ABL and plays an important role in protein folding and the function of BCR/ABL. Therefore, inhibiting the chaperone function of HSP90 may be an effective strategy for CML treatment and to overcome TKI resistance.MethodsThe effect of KW-2478 on CML cell viability, apoptosis and cell cycle progression was detected by CCK-8 assay or flow cytometry. The levels of BCR/ABL, HSP90 and other signalling proteins were detected by western blots. The mitochondrial membrane potential was detected by flow cytometry combined with JC-1 staining. The interaction between BCR/ABL and HSP90α was detected by coimmunoprecipitation. The effect of KW-2478 on BCR/ABL carcinogenesis in vivo was investigated in CML-like mouse models.ResultsKW-2478 inhibited growth and induced apoptosis of CML cells. KW-2478 inhibited the chaperone function of HSP90α and then weakened the BCR/ABL and MAPK signalling pathways. This treatment also caused an increase in p27 and p21 expression and a decrease in cyclin B1 expression, which led to G2/M phase arrest. The mitochondrial pathway was primarily responsible for KW-2478-induced apoptosis. KW-2478 had a synergistic effect with imatinib in growth inhibition. Notably, KW-2478 had a stronger effect on growth inhibition, apoptosis induction and cell cycle arrest of K562/G01 cells than K562 cells. KW-2478 could effectively prolong the mouse lifespan and alleviate disease symptoms in CML-like mouse models.ConclusionsThis finding demonstrated that KW-2478 had anticancer properties in imatinib-sensitive and imatinib-resistant CML cells and illustrated the possible mechanisms. This study provides an alternative choice for CML treatment, especially for TKI-resistant patients with BCR/ABL amplification and TKI-intolerant patients.

The evolution of the loss of life expectancy in patients with chronic myeloid leukaemia: a population-based study in the Netherlands, 1989-2018.

SummaryStudies on the conditional life expectancy of patients with chronic myeloid leukaemia (CML) are lacking. Using data from the Netherlands Cancer Registry, we examined the life expectancy of patients with CML in the Netherlands diagnosed during 1989–2018. As of the early 2010s, the life expectancy of patients with CML who survived several years after diagnosis came narrowly close to the general population’s life expectancy, regardless of age. This finding can essentially be ascribed to the introduction and broader application of tyrosine kinase inhibitors (TKIs) and provide optimism to patients with CML who can look forward to a near‐normal life expectancy in a modern TKI era.

Tyrosine kinase inhibitors as next generation oncological therapeutics: Current strategies, limitations and future perspectives

Protein kinases, a class of enzymes that govern various biological phenomena at a cellular level, are responsible for signal transduction in cells that regulate cellular proliferation, differentiation, and growth. Protein kinase enzyme mutation results in abnormal cell division leading to a pathological condition like cancer. Tyrosine kinase (TK) inhibitors, which helps as a potential drug candidate for the treatment of cancer, are continuously being developed. Majority of these drug candidates are being administered as conventional oral dosage form, which provides limited safety and efficacy due to non-specific delivery and uncontrolled biodistribution resulting into the adverse effects. A controlled drug delivery approach for the delivery of TK inhibitors may be a potential strategy with significant safety and efficacy profile. Novel drug delivery strategies provide target-specific drug delivery, improved pharmacokinetic behaviour, and sustained release leading to lower doses and dosing frequency with significantly reduced side effects. Along with basic aspects of tyrosine kinase, this review discusses various aspects related to the application of tyrosine kinase inhibitors in clinical oncological setting. Furthermore, the limitations/challenges and formulation advancements related to this class of candidates particularly for cancer management have been reviewed. It is expected that innovations in drug delivery approaches for TK inhibitors using novel techniques will surely provide a new insights for improved cancer treatment and patients' life quality.

Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

BackgroundThe pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy.MethodsAnti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML.ResultsThe results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo.ConclusionsIn conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

P28-functionalized PLGA nanoparticles loaded with gefitinib reduce tumor burden and metastases formation on lung cancer

Lung cancer is still the main cause of cancer-related deaths worldwide. Its treatment generally includes surgical resection, immunotherapy, radiotherapy, and chemo-targeted therapies such as the application of tyrosine kinase inhibitors. Gefitinib (GEF) is one of them, but its poor solubility in gastric fluids weakens its bioavailability and therapeutic activity. In addition, like all other chemotherapy treatments, GEF administration can cause damage to healthy tissues. Therefore, the development of novel GEF delivery systems to increase its bioavailability and distribution in tumor site is highly demanded. Herein, an innovative strategy for GEF delivery, by functionalizing PLGA nanoparticles with p28 (p28-NPs), a cell-penetrating peptide derived from the bacterial protein azurin, was developed. Our data indicated that p28 potentiates the selective interaction of these nanosystems with A549 lung cancer cells (active targeting). Further p28-NPs delivering GEF (p28-NPs-GEF) were able to selectively reduce the metabolic activity of A549 cells, while no impact was observed in non-tumor cells (16HBE14o-). In vivo studies using A549 subcutaneous xenograft showed that p28-NPs-GEF reduced A549 primary tumor burden and lung metastases formation. Overall, the design of a p28-functionalized delivery nanosystem to effectively penetrate the membranes of cancer cells while deliver GEF could provide a new strategy to improve lung cancer therapy.

Inhibition of GPX4 or mTOR overcomes resistance to Lapatinib via promoting ferroptosis in NSCLC cells

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in EGFR is a major driver force of lung cancer. EGFR tyrosine kinase inhibitors (TKIs) are group of promising agents to treat cancer patients with EGFR mutations. However, the application of TKIs is often hampered by the development of drug-resistance. In the present study, we studied the role of Glutathione peroxidase 4 (GPX4) and mammalian target of rapamycin (mTOR) in regulation of lung cancer cells response to Lapatinib (Lap). Lap resistant NSCLC cells A549/Lap and H1944/Lap were created and GPX4 was knockdown by lentivirus shGPX4. Change of cell viabilities and cell death were measured by MTT and flow cytometry, respectively. ROS, MDA, GSH and Fe2+ were detected by commercial kits. Xenograft mice was used to assay the in vivo effects of GPX4 on the sensitivity of Lap. We found that GPX4 and mTORC1 signalling was upregulated in Lap resistant NSCLC cells when compared to Lap sensitive NSCLC cells. Mechanistically, upregulation of GPX4 was due to enhanced activation of mTORC1 in Lap resistant NSCLC cells. Inhibition of mTORC1 led to the downregulation of GPX4 which promoted Lap induced ferroptosis as evidenced by increase of ROS, MDA, Fe 2+ and decrease of GSH. Rescue experiments confirmed the role of GPX4 in regulation of Lap induced ferroptosis. In vivo experiments also indicated that silencing of GPX4 enhanced the anticancer effect of Lap via promoting ferroptosis. Overall, targeting GPX4 might be a potential strategy to enhance antitumor effects of Lap.

Effects of FGFR Tyrosine Kinase Inhibition in OLN-93 Oligodendrocytes.

Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG35–55-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS.

Targeting protein lysine methyltransferase G9A impairs self-renewal of chronic myelogenous leukemia stem cells via upregulation of SOX6.

The application of tyrosine kinase inhibitors (TKIs) in clinic has revolutionized chronic myelogenous leukemia (CML) treatment, but fails to eliminate leukemia stem cells (LSCs), which are considered as roots of drug resistance and disease relapse. Thus, eradication of LSCs may be a promising strategy for curing CML. In this study, we found that protein lysine methyltransferase G9A was overexpressed in CML LSCs. The upregulation of G9A by BCR-ABL was independent on its tyrosine kinase activity. Knockdown of G9A by shRNAs or pharmacological inhibition of G9A by UNC0642 significantly suppressed survival and impaired self-renewal capacity of CML LSCs. Inhibition of G9a eradicated LSCs in CML mice driven by BCR-ABL gene and dramatically prolonged survival of the mice. Ex vivo treatment with G9A inhibitor inhibited long-term engraftment of CML CD34+ cells in immunodeficient mice. Mechanically, tumor suppressor SOX6 was identified as a direct target of G9A in CML LSCs by RNA-seq analysis. Silencing Sox6 at least partially rescued G9a knockdown-mediated LSCs elimination in vivo. Our findings improve the understanding of LSC regulation network and validate G9A as a therapeutic target in CML LSCs. Targeting G9A may be considered as an additional strategy for the treatment of patients with CML.

Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Nanomedicine of tyrosine kinase inhibitors.

Recent progress in nanomedicine and targeted therapy brings new breeze into the field of therapeutic applications of tyrosine kinase inhibitors (TKIs). These drugs are known for many side effects due to non-targeted mechanism of action that negatively impact quality of patients' lives or that are responsible for failure of the drugs in clinical trials. Some nanocarrier properties provide improvement of drug efficacy, reduce the incidence of adverse events, enhance drug bioavailability, helps to overcome the blood-brain barrier, increase drug stability or allow for specific delivery of TKIs to the diseased cells. Moreover, nanotechnology can bring new perspectives into combination therapy, which can be highly efficient in connection with TKIs. Lastly, nanotechnology in combination with TKIs can be utilized in the field of theranostics, i.e. for simultaneous therapeutic and diagnostic purposes. The review provides a comprehensive overview of advantages and future prospects of conjunction of nanotransporters with TKIs as a highly promising approach to anticancer therapy.

Tyrosine kinase inhibitors in the treatment of advanced lung cancer from example of preferential medicine provision in Moscow city

Lung cancer is leading cause of death across oncological diseases. Nowadays, the therapy of lung cancer remains most serious problem of oncology. Targeted therapy including tyrosine kinase inhibitors (TKIs) is widely used in current clinical practice to treat advanced or metastatic non-small cell lung cancer. This paper reviews the clinical aspects of TKIs application in practical medicine. The article summarizes the results and outcomes of key clinical trials focused on efficiency and safety of TKIs, describes the results of analysis for TKIs need within the Moscow City Department of Healthcare system providing preferential medicines. The perspectives of future clinical developments of targeted treatments for lung cancer are postulated and discussed as well. Our previously unpublished data clearly demonstrate that gefitinib, erlotinib and afatinib turned out to be the most used TKIs for treatment of non-small cell lung cancer in the system of preferential medicine supply for Moscow population in 2018. The choice of targeted drugs directly depends on the molecular genetic profile of the tumor. To further improve the use of financial resources of the Moscow City Department of Healthcare it is essential to define accurately the molecular profile of the tumor specimens and prescribe the most effective TKIs for each individual case of lung cancer.

Progress of MM/CML treatment and medical economics

Cost-effectiveness of the sequential application of tyrosine kinase inhibitors (TKIs) is an important issue in chronic myelogenous leukemia (CML). Similarly, although overall survival (OS) has tremendously improved, the treatment of multiple myeloma (MM), including 12 new drugs, typically costs more than $100,000 per year. This price should not be judged in isolation but rather evaluated in the context of clinical benefit, which can be assessed by cost-effectiveness analyses such as the total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Physicians change drugs several times to prolong individual patient survival over the course of their therapy, which means there are variations in treatment choices and treatment sequence. To achieve a clinical response by each treatment is very important, and the overall response rate and OS are key pieces of information to assess this. The additional treatment goal is sustained minimal residual disease (MRD) negativity. In Japan, medical costs for MM are mostly covered by public health insurance. Modifications in treatment patterns for CML and MM drugs and medical costs for patients are important issues; how to cure the disease or prolong the therapy-free interval with lower costs is an urgent requirement. Total medical costs have remained stable since 2010, but there are important issues to consider in the use of generic drugs, Phase 2 approval of new drugs, and decreasing costs of other care, particularly for hospitalization that includes treatment costs other than that of CML and MM drugs. We must aim for treatment-free remission and a clinical cure in the future. We can stop treatment with a 2-year sustained molecular response (MR)4.5 in CML and MRD negative (<10-5) in MM with full informed consent and careful watch by the BCR-ABL international scale and next-generation flow.

Reduced expression of CYLD promotes cell survival and inflammation in gefitinib-treated NSCLC PC-9 cells: Targeting CYLD may be beneficial for acquired resistance to gefitinib therapy.

The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non-small-cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR-TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR-TKI resistance remains elusive. Here, we found CYLD was upregulated in PC-9 cells, whereas downregulated in PC-9 acquired gefitinib-resistant (PC-9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC-9/GR cells than that in PC-9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin-6, transforming growth factor-β and tumor necrosis factor-α, which may contribute to acquired resistance of PC-9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC-9/GR cells downregulated CYLD expression, enhanced subsequent CYLD-dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib-resistant treatment in NSCLC.

The research status and development trend of EGFR gene exon 20 insertion mutant non-small cell lung cancer

The successful application of tyrosine kinase inhibitor (TKI) has kicked off the targeted therapy of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) since the discovery of EGFR gene mutations. Patients harboring the two most classic representative mutations of EGFR gene including exon 19 in-frame deletion or exon 21 L858R mutation could get significant clinical benefits from EGFR-TKIs compared to traditional chemotherapy. Among other approximately 10% of EGFR gene mutation type, exon 20 insertion occupies the first place. Available research had demonstrated that EGFR exon 20 insertion in NSCLC was highly malignant and most insertion variants showed de novo drug resistance towards current approved 1(st) to 3(rd) generation EGFR-TKIs, with much poorer clinical prognosis. Currently, there is a lack of comprehensive research and clinical guideline on the treatment of this specific mutation. In this article, we review the pathogenesis, amino acid sequence variants and current management of EGFR exon 20 insertion mutant NSCLC. Moreover, we come up with the emphasis on the treatment challenges and further development of this rigid mutation in NSCLC.