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Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm typically characterized by the presence of the Philadelphia chromosome. The advent of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of most CML patients. However, resistance to TKIs poses a significant challenge, leading to poor treatment outcomes and prognosis in some patients. Fortunately, the introduction of asciminib, a novel allosteric BCR-ABL1 inhibitor, has provided a ray of hope. We present three cases in this report that highlight the remarkable efficacy of asciminib seen in our patients. All of these patients initially responded positively to conventional TKIs but developed a T315I mutation in the BCR-ABL fusion protein during their chemotherapy, rendering conventional TKIs ineffective and resulting in loss of response. Asciminib led to the achievement of a major molecular response in all of our patients.
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Objective:To investigate the efficacy and safety of different transcatheter arterial chemoembolization(TACE)-based regimens in patients with unresectable hepatocellular carcinoma(uHCC)and explore the optimal timing for combining TACE with tyrosine kinase inhibit-ors(TKIs)and immune checkpoint inhibitors(ICIs).Methods:A retrospective analysis was conducted on data from 555 patients with uHCC who underwent TACE-based treatment between April 2016 and December 2021 in Nanfang Hospital,Southern Medical University.The pa-tients were assigned into the following four groups according to different treatment regimens:TACE group(n=317),TACE combined with TKIs group(TACE+TKIs,n=66),TACE combined with ICIs group(TACE+ICIs,n=33),and TACE combined with TKIs+ICIs group(TACE+TKIs+ICIs,n=139).Subgroup analysis was performed within the TACE+TKIs+ICIs group,with patients being assigned into"pre-TACE"and"post-TACE"groups based on the timing of the combination therapy.Univariate and multivariate Cox regression analyses were conducted to identify pro-gnostic factors influencing overall survival(OS).Results:The TACE+TKIs+ICIs group showed the longest OS(21.9 months,95%confidence in-terval[CI]:17.2-26.6,P=0.030)and progression-free survival(PFS)(8.3 months,95%CI:7.3-9.3,P=0.004)compared to those in the other three groups.In the subgroup analysis,the"post-TACE"group had longer OS than the"pre-TACE"group(26.8 months vs.19.2 months,P = 0.011).The objective response rate(ORR)was 32.8%,41.1%,42.4%,and 52.5%(P=0.001)and the disease control rate(DCR)was 59.6%,71.2%,69.7%,and 82.7%(P<0.001)in the TACE,TACE+TKIs,TACE+ICIs,and TACE+TKIs+ICIs groups,respectively.The adverse events were similar to those reported in previous studies.Cox regression analysis revealed that tumor number,extrahepatic metastasis,and treatment regimen were independent factors influencing OS in patients(all P<0.05).Conclusions:TKIs or ICIs can improve OS and PFS in patients with uHCC receiving TACE,and the combination of TKIs+ICIs with TACE achieves better beneficial outcomes.The greatest OS was observed when the combination therapy TKIs+ICIs was initiated within 3 months after the first TACE procedure.
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The chromosomal abnormality of Philadelphia chromosome is mostly seen in Chronic Myeloid Leukemia (CML). But it is observed that the Philadelphia chromosome (Ph), t(9,22), is the most common cytogenetic abnormality in adult patients with acute lymphoblastic leukemia (ALL), occurring in about 20% to 30 % of all cases. Patients with Ph-positive ALL have breaks in the minor breakpoint region, m?BCR (exons 1?2) lead to a short fusion proteins (p190) and is most frequently associated with Ph chromosome- positive ALL. They have an increased risk for central nervous system (CNS) involvement, an aggressive clinical course and poor prognosis. Historically, they had an inferior outcome when compared with their Ph-negative counterparts. Adult Ph+ patients achieve Complete Remission rates comparable to Ph? ALL patients with standard chemotherapy, but the remissions are short and survival poor. The addition of tyrosine kinase inhibitors (TKIs) including imatinib has dramatically improved outcomes. We are presenting this case report of t(9;22), p190 BCR-ABL1 positive ALL in an elderly female patient of south Gujarat.
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BACKGROUND@#The incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients.@*METHODS@#Between 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0.@*RESULTS@#In total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20<cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20>cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P<0.001).@*CONCLUSIONS@#Patients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.
الموضوعات
Humans , Carcinoma, Non-Small-Cell Lung/radiotherapy , ErbB Receptors/genetics , Lung Neoplasms/radiotherapy , Protein Kinase Inhibitors/adverse effects , Pulmonary Disease, Chronic Obstructive/complications , Radiation Pneumonitis/etiology , Radiotherapy Dosage , Retrospective Studiesالملخص
Epidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characEpidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characteristics and clinical efficacy of the third-generation EGFR TKIs in the market or in the clinical development. Then this article summarizes the detailed mechanisms behind the acquired drug resistance of third-generation EGFR TKIs，and further expounds the current treatment strategies to overcome the resistance. Collectively, this review could provide more information for the development and clinical application of drugs targeting EGFR.
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@#[ 摘 要 ] 表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor，EGFR-TKI）的上市， 使治疗EGFR 突变的晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）患者的客观有效率达到79%，取得了显著的抗肿瘤 治疗效果。然而，耐药是EGFR-TKIs 治疗的瓶颈，对耐药机制的研究以及耐药后的治疗策略，成为肺癌治疗的难点和热点问 题。随着免疫治疗的兴起，越来越多的证据发现，PD-L1 不仅与EGFR 基因突变之间存在调节关系，而且PD-L1 表达和EGFR-TKIs 耐药也显示出新的相关性。探究PD-L1 表达与EGFR-TKIs 耐药之间的关系对寻找EGFR-TKIs 耐药后治疗策略具有重要意义。
الملخص
Epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKIs) has been mainly used for molecular targeted therapy of advanced non-small cell lung cancer. With the deeper and deeper research of EGFR-TKIs it was found that EGFR and its ligands were involved in the pathogenesis of different human cancers, such as breast cancer and pancreatic cancer. Therefore, the treatment of EGFR-TKIs is no longer limited to advanced non-small cell lung cancer, it also has a good inhibitory effect on malignant tumors such as breast cancer, pancreatic cancer, head and neck cancer, esophageal cancer and cervical cancer. Combination medications are often more effective than medication alone. The article discusses the application research of EGFR-TKIs in the treatment of cancers other than lung cancer and the potential application prospects of EGFR-TKIs combined with other drugs in the treatment of breast cancer, pancreatic cancer and other malignant tumors.
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AIM: To investigate the sensitization of flavonoids from Tetrastigma hemsleyanum (FTH) on gefitinib (GEF)-resistant lung adenocarcinoma cells. METHODS: The viabilities of A549 and A549/GR cells treated with FTH and GEF were detected by MTT method. The apoptotic rates and cell cycles of A549/GR cells treated with FTH and GEF were detected by Flow cytometry. The anti-tumor effects of flavonoids from FTH and GEF were assayed in A549/GR tumor-bearing mice. The expressions of proteins (PTEN, PI3K, p-PI3K, AKT, p-AKT) were detected by Western blot analysis. RESULTS: Compared with GEF group, FTH significantly enhanced the inhibition of GEF on the proliferation of A549/GR cells (P< 0.05). Combination with FTH and GEF significantly increased the apoptosis of A549/GR cells which were arrested at the G
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Anti-angiogenesis-targeted drugs, especially anti-angiogenic tyrosine kinase inhibitors (aa-TKIs), are broadly used in the treatment of advanced bone and soft tissue sarcoma. The antitumor effects of Chinese domestically developed aa-TKIs, such as apatinib and anlotinib, were also demonstrated in several single-center or multi-center clinical studies. However, treatment-related adverse events (AEs) have limited the use of aa-TKIs. On Aug 30, 2019, the members of the Chinese Sarcoma Study Group conducted a thorough discussion on this issue and reached a consensus, focusing on the classification and treatment of common AEs that may occur during the use of aa-TKIs. The aim of this article is to improve our understanding and provide AE management guidance for clinicians as well as benefit patients using aa-TKIs.
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Objective: To compare overall survival (OS) and intracranial progression-free survival (iPFS) effects of whole-brain radiotherapy (WBRT) and tyrosine kinase inhibitors (TKIs) in NSCLC patients with brain metastases (BM) stratified by EGFR mutation status (mutant, wild-type). Methods: We performed a retrospective analysis of 215 NSCLC BM patients diagnosed in January 2013 to January 2015 with known EGFR status and followed up to December 1, 2016. Stratified Kaplan-Meier curves and multivariate Cox models were used to evaluate the effects of WBRT (defined as≥30 Gy, "W") and TKIs (after BM, "T") on OS and iPFS independently and jointly. Two-sided P>0.20 was considered non-significant (ns). Results: In patients with BM, the mean age was 58 years, 52% were female, and 93% had adenocarcinoma. Those with EGFR mutations (114 patients) had "W" (35 patients) and "T" (87 patients) with adjusted hazard ratios (HRs) (P) of 1.135 (ns) and 0.202 (P<0.001) for OS, respectively, and 1.122 (ns) and 0.275 (P<0.001) for iPFS, respectively. "W+T" (22 patients), "T only" (65 patients), "W only"(13 patients), and "neither" (14 patients) had OS-median survival time (MST) of 14.1, 15.3, 7.1, and 4.3 months, respectively; their iPFS-MST were 14.1, 13.4, 6.8, and 4.5 months, respectively. Their adjusted HRs (P) were 0.196 (P=0.003), 0.114 (P<0.001), 0.434 (ns), 1.000 (ref) for OS, respectively, and 0.272 (P=0.012), 0.200 (P<0.001), 0.622 (ns), 1.000 (ref) for iPFS, respectively. Compared with "T only," "W+T" was not associated with better survival and "W only" had adjusted HRs (P) of 3.804 (P=0.025) for OS and 3.114 (P=0.032) for iPFS. The EGFR wild-type (101 patients) used "W" in 43 patients with OS-MST of 11.3 (7.1) and iPFS of 11.2 (4.8) months; the adjusted HRs (P) of "W"were 0.539 (P=0.105) for OS and 0.485 (P=0.048) for iPFS. Conclusions: In EGFR-mutant NSCLC BM patients, TKIs are associated with improved survival, whether, WBRT alone or combined are not. In cases of EGFR wild-type, WBRT confers the improved the iPFS.
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BACKGROUND@#Adenocarcinoma is the most common type of lung cancer. It has been clinically evaluated that therapiestargeting against the epidermal growth factor receptor (EGFR) as the clinical standard first-line treatment. The response and outcome of EGFR-tyrosine kinase inhibitors (TKIs) in patients harboring common mutations in EGFR kinase domain (deletion in exon19 and L858R in exon 21) has been well demonstrated, but not in rare or complex mutations.@*METHODS@#A total of 150 patients that harbored rare or complex mutations in EGFR diagnosed by histopathology were included in this retrospective study. The clinical-pathological characteristics of all 150 patients as well as the response and progression-free survival (PFS) in 48 patients that received EGFR-TKIs in first/second/third line treatments weredescribed and analyzed.@*RESULTS@#Patients were divided into four groups based on the mutation types: single G719X point mutation in exon 18 (n=46, 30.7%), single L861Q point mutation in exon 21 (n=45, 30.0%), other single rare mutation (n=14, 9.3%) and complex mutations (n=45, 30.0%). The result indicated thatthere was no correlation of EGFR mutation typeswith other parameters such as gender, age, clinical stage, pathology and smoking history. For the 48 patients that received EGFR-TKIs treatment, there were no significant differencesamong 4 groups in terms of objective response rate (ORR) and disease control rate (DCR) (54.5% vs 30.0% vs 0.0% vs 35.7%, χ²=3.200, P=0.34; 90.9% vs 85.0% vs 66.7% vs 92.9%, χ²=2.162, P=0.59). The median progress-free survival (mPFS) was 11.0 months (95%CI: 4.4-17.6), and in each group of different EGFR mutation types are 15.8 months (95%CI: 9.5-22.2), 8.0 months (95%CI: 5.1-11.0), 4.9 months (95%CI: 1.4-8.4) and 23.1 months (95%CI: 15.8-30.4)(χ²=7.876, P=0.049).@*CONCLUSIONS@#The efficiency of targeting EGFR-TKIs on different types of rare or complex mutations was heterogeneous. The PFS may be better in patients that harbored complex mutations than those with single rare mutations. Further studies with larger sample size are necessary. Moreover, to discover novel therapeutic targets and develop new drugs are imminentfor those patientswith no response to the existing treatments.
الموضوعات
Female , Humans , Male , Middle Aged , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Genetics , Disease-Free Survival , ErbB Receptors , Genetics , Exons , Genetics , Lung Neoplasms , Drug Therapy , Genetics , Mutation , Protein Kinase Inhibitors , Pharmacology , Therapeutic Uses , Retrospective Studies , Treatment Outcomeالملخص
BACKGROUND@#There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or Kelch-like ECH-associated protein 1 (Keap1) in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different "driver gene" is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients.@*METHODS@#Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type.@*RESULTS@#The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P0.05). The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05). The progression -free survival (PFS) and overall survival (OS) of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05). Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05).@*CONCLUSIONS@#The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly correlated with PFS and OS of EGFR-TKIs. Therefore, Nrf2 may be a biomarker for predicting response of EGFR-TKIs and a potential target for overcoming resistance of EGFR-TKIs.
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Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Adenocarcinoma , Drug Therapy , Genetics , Metabolism , Pathology , Adenocarcinoma of Lung , ErbB Receptors , Genetics , Metabolism , Kelch-Like ECH-Associated Protein 1 , Genetics , Metabolism , Lung Neoplasms , Drug Therapy , Genetics , Metabolism , Pathology , Mutation , NF-E2-Related Factor 2 , Genetics , Metabolism , Neoplasm Staging , Protein Kinase Inhibitors , Therapeutic Usesالملخص
Lung cancer is the one of the malignant tumor of the highest morbidity and mortality over the world, and non-small cell lung cancer (NSCLC) makes up about 80%. Nowadays, molecular targeted therapy has been the first-line treatment for NSCLC. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are increasingly used in the clinical treatment, but the EGFR-TKIs acquired resistance becomes the bottleneck of continuation of EGFR-TKIs therapy. Epithelial-mesenchymal transition (EMT) is a biological phenomenon in which epithelial cells are transformed into mesenchymal cells. EMT promoted metastasis, invasion of lung cancer and conferred characteristic of stem cell on cancer cells. Meanwhile, EMT is one of an important cause of EGFR-TKIs resistance in NSCLC. The recent studies have found that resistant cells restored the sensitivity to EGFR-TKIs by reversing EMT which suggested that the target of EMT may contribute to inhibit or even reverse the resistance of EGFR-TKIs. Here we make a review about research progress of EMT in EGFR-TKIs resistance in NSCLC. .
الموضوعات
Animals , Humans , Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Genetics , Metabolism , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , ErbB Receptors , Genetics , Metabolism , Lung Neoplasms , Drug Therapy , Genetics , Metabolism , Protein Kinase Inhibitorsالملخص
The effects of tyrosine kinase inhibitors (TKIs) were evaluated on growth inhibition of intracellular Toxoplasma gondii in host ARPE-19 cells. The number of tachyzoites per parasitophorous vacuolar membrane (PVM) was counted after treatment with TKIs. T. gondii protein expression was assessed by western blot. Immunofluorescence assay was performed using Programmed Cell Death 4 (PDCD4) and T. gondii GRA3 antibodies. The TKIs were divided into 3 groups; non-epidermal growth factor receptor (non-EGFR), anti-human EGFR 2 (anti-HER2), and anti-HER2/4 TKIs, respectively. Group I TKIs (nintedanib, AZD9291, and sunitinib) were unable to inhibit proliferation without destroying host cells. Group II TKIs (lapatinib, gefitinib, erlotinib, and AG1478) inhibited proliferation up to 98% equivalent to control pyrimethamine (5 μM) at 20 μM and higher, without affecting host cells. Group III TKIs (neratinib, dacomitinib, afatinib, and pelitinib) inhibited proliferation up to 98% equivalent to pyrimethamine at 1–5 μM, but host cells were destroyed at 10–20 μM. In Group I, TgHSP90 and SAG1 inhibitions were weak, and GRA3 expression was moderately inhibited. In Group II, TgHSP90 and SAG1 expressions seemed to be slightly enhanced, while GRA3 showed none to mild inhibition; however, AG1478 inhibited all proteins moderately. Protein expression was blocked in Group III, comparable to pyrimethamine. PDCD4 and GRA3 were well localized inside the nuclei in Group I, mildly disrupted in Group II, and were completely disrupted in Group III. This study suggests the possibility of a vital T. gondii TK having potential HER2/4 properties, thus anti-HER2/4 TKIs may inhibit intracellular parasite proliferation with minimal adverse effects on host cells.
الموضوعات
Humans , Antibodies , Blotting, Western , Cell Death , Epidermal Growth Factor , Erlotinib Hydrochloride , Fluorescent Antibody Technique , Membranes , Parasites , Protein-Tyrosine Kinases , Pyrimethamine , ErbB Receptors , Toxoplasmaالملخص
OBJECTIVES: In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Único de Saúde (SUS). We studied the socio-demographic factors that influenced therapy success in a population in the northeast region of Brazil. METHODS: Patients with chronic myeloid leukemia from the state of Piauí were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient's home to the hospital, years of formal education and monthly income. RESULTS: Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase) in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not. CONCLUSION: Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment. .
الموضوعات
Comparative Effectiveness Research/methods , Bayes Theorem , Defibrillators, Implantable/statistics & numerical data , Mammography/statistics & numerical dataالملخص
Thoracic radiotherapy is an important means of local treatment for non -small cell lung cancer (NSCLC).Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)have the effect of systemic therapy.Studies have shown that NSCLC patients with EGFR exons 19,21 mutation have a synergistic effect in the combination therapy .Radiotherapy activates EGFR signaling pathway ,inducing cell proliferation and DNA damage repair,leading to radiation resistance .Therefore,EGFR-TKIs have the effect in increasing radiosensitivity .Lung injury is one of the most common side effects when the two therapies combined .Studies suggest that radiotherapy combined with EGFR-TKIs may have conflicting functions in the development of pulmonary fibrosis ,the discrep-ancy between these studies may depend on the differences in the experimental systems ,the differences in pulmo-nary fibrosis models,as well as the differences between different species and individuals .Therefore,a more com-plete understanding of the etiology for pulmonary fibrosis is necessary to the development of improved treatments .
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BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the recommended treatment for patients with chronic myeloid leukemia (CML). The MDR1/ABCB1 gene plays a role in resistance to a wide spectrum of drugs, including TKIs. However, the association of MDR1/ABCB1 gene polymorphisms (SNPs) such as C1236T, G2677T/A, and C3435T with the clinical therapeutic evolution of CML has been poorly studied. We investigated these gene polymorphisms in CML-patients treated with imatinib, nilotinib and/or dasatinib. METHODS: ABCB1-SNPs were studied in 22 CML-patients in the chronic phase (CP) and 2 CML-patients in blast crisis (BC), all of whom were treated with TKIs, and compared with 25 healthy controls using nested-PCR and sequencing techniques. RESULTS: Seventeen different haplotypes were identified: 7 only in controls, 6 only in CML-patients, and the remaining 4 in both groups. The distribution ratios of homozygous TT-variants present on each exon between controls and CML-patients were 2.9 for exon 12, and 0.32 for the other 2 exons. Heterozygous T-variants were observed in all controls (100%) and 75% of CML-patients. Wt-haplotype (CC-GG-CC) was observed in 6 CML-patients (25%). In this wt-group, two were treated with nilotinib and reached a major molecular response. The remaining 4 cases had either a minimal or null molecular response, or developed bone marrow aplasia. CONCLUSION: Our results suggest that SNPs of the MDR1/ABCB1 gene could help to characterize the prognosis and the clinical-therapeutic evolution of CML-patients treated with TKIs. Wt-haplotype could be associated with a higher risk of developing CML, and a worse clinical-therapeutic evolution.
الموضوعات
Humans , Blast Crisis , Bone Marrow , Exons , Haplotypes , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Polymorphism, Single Nucleotide , Prognosis , Protein-Tyrosine Kinases , Dasatinib , Imatinib Mesylateالملخص
Objective: To investigate the role of EMT (epithelial-mesenchymal transition) and IGF- 1R (insulin-like growth factor I receptor) in acquired resistance to EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) in NSCLC (non-small cell lung cancer). Methods: The EGFR mutant human lung adenocarcinoma PC-9 cell line and the EGFR wild-type H460 cell line were used to generate gefitinib-resistant PC-9 cells (named as PC-9/ZD cells) and erlotinib-resistant cells (named as H460/ER cells), respectively. MTT assay was used to measure the cell proliferation of PC9, PC-9/ZD, H460 and H460/ER cells. Wound-healing assay and Transwell assay were used to determine the migration and invasion capabilities of the cells. The protein and mRNA expressions of E-cadherin, vimentin, EGFR, ERK (extracellular signal-regulated kinase), AKT (protein kinase B) and IGF-1R were determined by Western blotting and RT-PCR (reverse transcription PCR), respectively. Results: Both PC-9/ZD and H460/ER cells acquired resistance to EGFR-TKIs which was to say that the sensitivities to gefitinib and erlotinib in PC-9/ ZD and H460/ER cells were significantly decreased, respectively (P < 0.05). Compared with PC-9 and H460 cells, the PC-9/ZD and H460/ER cells displayed mesenchymal phenotypes, and their capabilities of invasion and migration were enhanced (P < 0.05). The expression of mesenchymal cell marker vimentin was increased in both PC-9/ZD and H460/ER cells (P < 0.05), and the expression of E-cadherin was decreased in PC-9/ZD cells (P < 0.05). The expressions of IGF-1R and its phosphorylated form in both PC-9/ZD and H460/ER cells were significantly increased (P < 0.05) as compared with those in the PC-9 and H460 cells, accompanied by up-regulation of phosphorylation levels of AKT and ERK (P < 0.05). No significant difference was found in phosphorylation level of EGFR between PC-9 and PC-9/ZD cells (P < 0.05), while the phosphorylation level of EGFR was significantly decreased in H460/ER cells as compared with that in H460 cells (P < 0.05). Conclusion: The EMT in EGFR mutant gefitinib-resistant PC-9/ZD cells and the EGFR wild-type erlotinib-resistant H460/ER cells was accompanied by a increase in protein expression of IGF-1R, which suggests EMT and IGF-1R signal transduction may play an important role in acquired resistance to EGFR-TKIs in NSCLC cells. Copyright © 2013 by TUMOR.
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Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in some cancers, but not in hepatocellular carcinoma (HCC). The aim of this study was to investigate the drug potential to overcome multi-drug resistance in HCC cells. Thirteen drug-sensitive HCC cells were assessed using the CCK-8 assay. G0-G1 arrest was measured by FACS. Western blot analysis was used to detect the key enzymes in both the Ras/Raf and PI3K pathways. When establishing the IC50 of HCC to several drugs, including EKB-569, sorafenib, erlotinib, gefitinib, pazopanib, and brivanib, SK-Hep1 cells treated with EKB-569 have shown the highest (72.8%-86.4%) G0-G1 arrest and decreased the phosphorylation of AKT and ERK at the protein level. We found that EKB-569 had higher efficacy in HCC, compared to first generation, reversible EGFR-TK inhibitors. Furthermore, the combination of sorafenib and EKB-569 showed a synergistic effect to inhibit proliferation of SNU-475, previously the most resistant cell to EGFR-TKIs. Therefore, novel EKB-569 in combination with sorafenib may be able to overcome HCC resistance to EGFR-TK inhibitors.