Auranofin reverses acquired resistance to osimertinib in non-small cell lung cancer / 中国药理学通报

Aim To investigate the role of auranofin in reversing acquired resistance to osimertinib in non-small cell lung cancer. Methods Osimertinib-sensi-tive NSCLC cell lines HI975 and PC9 were used to establish osimertinib-resistant NSCLC cell lines HI975/OR and PC9/OR. An FDA approved library of 1470 FDA drugs was used to high-throughput screen the reversal agents of acquired resistant of osimertinib by CCK-8. Compusyn was used to calculate the combination index of osimertinib and auranofin to determine the optimal dose of drug combination. CCK-8, EdU, flow cytometry and Transwell experiments were used to detect osimertinib, auranofin and the combination drug effect on proliferation, apoptosis, migration and invasion of osimertinib acquired NSCLC cell lines. RNA-sequencing was applied to screen differentially expressed mRNAs in osimertinib treatment alone and osimertinib combined with auranofin treatment group. qRT-PCR and western blot were employed to validate the selected gene expression and protein expression. Results Compared with osimertinib sensitive cell lines H1975 and PC9, H1975/OR and PC9/OR showed significantly higher cell viability and lower apoptosis rate after osimertinib treatment. The resistance index was 70. 31 and 136. 99, respectively. In FDA approved 1470 drug library, only auranofin could enhance the sensitivity of osimertinib in H1975/OR and PC9/OR. When 1 μmol • L

Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By knocking in L156F into cancer cells using CRISPR/Cas9, we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors, not only ATP competitive inhibitor but also PROTAC degrader. Mechanistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

Mecanismos de expressão de resistência aos antibióticos e saúde pública / Mechanisms of expression of resistance to antibiotics and public health / Mecanismos de expresión de la resistencia a los antibióticos y salud pública

Com o avanço da medicina e o aumento do uso de antimicrobianos, a resistência microbiana vem se tornando um problema sério na saúde pública. Para que uma bactéria se torne resistente, são necessários vários fatores, entre eles, o uso indiscriminado e prolongado de antimicrobianos e as resistências intrínsecas e adquiridas. Nesse contexto, o objetivo do trabalho foi explorar os mecanismos de ação dos antimicrobianos, de resistência e a sua importância na saúde pública. Foram utilizadas para a presente pesquisa, as bases de dados Pubmed, Google acadêmico e Scielo. Segundo a Organização Mundial da Saúde define-se resistência ao antibiótico quando o mesmo não produz mais efeito. A inserção cada vez mais frequente de antimicrobianos favorece a resistência, onde provocam uma pressão seletiva sobre os microrganismos, tornando-os resistentes a diversas drogas. O uso indiscriminado de antimicrobianos é o principal fator de resistência microbiana, assim como o uso de antimicrobianos sem exame de cultura e teste de sensibilidade. Neste sentido, conclui-se que é de suma importância a atualização de protocolos que contenham os mecanismos de resistência bacteriana a fim de minimizar o uso indiscriminado de antimicrobianos, assim como capacitar os profissionais da saúde para este problema na saúde pública.

With the advance of medicine and the increase in the use of antimicrobials, microbial resistance has become a serious problem in public health. For a bacterium to become resistant, several factors are necessary, among them, the indiscriminate and prolonged use of antimicrobials and the intrinsic and acquired resistance. In this context, the objective of the work was to explore the mechanisms of action of antimicrobials, resistance and their importance in public health. Pubmed, Google academic and Scielo databases were used for this research. According to the World Health Organization, resistance to antibiotics is defined when it no longer has an effect. The increasingly frequent insertion of antimicrobials favors resistance, where they put selective pressure on microorganisms, making them resistant to various drugs. The indiscriminate use of antimicrobials is the main factor of microbial resistance, as well as the use of antimicrobials without culture examination and sensitivity test. In this sense, it is concluded that it is extremely important to update protocols that contain the mechanisms of bacterial resistance in order to minimize the indiscriminate use of antimicrobials, as well as to train health professionals for this problem in public health.

Con los avances de la medicina y el mayor uso de antimicrobianos, la resistencia microbiana se ha convertido en un grave problema de salud pública. Para que una bacteria se vuelva resistente son necesarios varios factores, entre ellos, el uso indiscriminado y prolongado de antimicrobianos y la resistencia intrínseca y adquirida. En este contexto, el objetivo de este trabajo fue explorar los mecanismos de acción de los antimicrobianos, la resistencia y su importancia en la salud pública. Para esta investigación se utilizaron las bases de datos Pubmed, Google Scholar y Scielo. Según la Organización Mundial de la Salud, la resistencia a un antibiótico se define cuando deja de producir efecto. El uso cada vez más frecuente de antimicrobianos favorece la resistencia, ya que provocan una presión selectiva sobre los microorganismos, haciéndolos resistentes a varios fármacos. El uso indiscriminado de antimicrobianos es el principal factor de resistencia microbiana, así como el uso de antimicrobianos sin pruebas de cultivo y sensibilidad. En este sentido, se concluye que es de suma importancia actualizar los protocolos que contienen los mecanismos de resistencia bacteriana para minimizar el uso indiscriminado de antimicrobianos, así como capacitar a los profesionales de la salud para este problema en la salud pública.

Research progress of Osimertinib acquired resistance / 中国临床药理学与治疗学

Osimertinib, as a representative of the third generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has significant curative effect for EGFR T790M mutation type non-small cell lung cancer (NSCLC). But with the development of clinical research Osimertinib's resistance gradually appear. How to deal with the resistance is a problem that the clinical workers must focus on. This article will review the latest research progress of the mechanisms and the solutions of osimertinib acquired resistance.

Gene Fusions as Acquired Resistance Mechanisms of EGFR-TKI / 中国肺癌杂志

Patients with sensitive epidermal growth factor receptor (EGFR) mutations often respond to tyrosine kinase inhibitors (TKIs), but acquired resistance will eventually develop. The most common mechanisms of acquired resistance include secondary EGFR mutation, MET amplification, and histologic transformation. Besides, gene fusions could also mediate the process of acquired resistance. Various gene fusions including rearranged during transfection (RET), v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and anaplastic lymphoma kinase (ALK) could take place after TKIs resistance, the incidence of which is around 1%. The clinical cases and experiments both in vitro and in vivo have proved the role of gene fusions in EGFR-TKI resistance. The combination of EGFR inhibitors and gene fusion inhibitors might be an effective therapeutic method. The understanding of gene fusions at EGFR-TKI resistance may contribute to the subsequent diagnosis and treatment strategy.

Advances in the mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer / 药学学报

Lung cancer ranks the first in the mortality rate among all cancers, and non-small cell lung carcinoma (NSCLC) accounts for about 80% of the incidence of lung cancer. In recent years, the drugs targeting specific molecules have been developed rapidly. The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved good results in the treatment of patients with NSCLC. Currently, there are three generations of EGFR-TKIs, and the treatment outcome of these drugs surpasses traditional chemotherapies. However, the problems of acquired resistance remains in the course of treatment. In this review, research progress of the mechanisms of acquired resistance is divided into two parts: EGFR-dependent pathway and EGFR-independent pathway. The EGFR-dependent pathway mainly includes EGFR gene mutations, whereas the EGFR-independent pathways include HER2 amplification, BIM deletion, activation of HGF/c-Met pathway, activation of IGF1R, RAS mutation, PTEN deletion, epithelial-mesenchymal transition, PUMA loss, and high levels of expression of VEGF or IL-6. These interconnected mechanisms are linked with acquired resistance to EGFR-TKIs in NSCLC.

Role of EZH2 Inhibitor Combined with Gefitinib in EGFR-TKIs Resistant Lung Cancer Cells / 中国肺癌杂志

BACKGROUND@#Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells.@*METHODS@#PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression.@*RESULTS@#In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins.@*CONCLUSIONS@#The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.

Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1. MATERIALS AND METHODS: We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3′ mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines. RESULTS: We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)‒dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit α (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase α (PI3Kα) inhibitor. CONCLUSION: Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.

Establishment of an osimertinib-resistant human non-small cell lung cancer cell line and its subsequent sensitivity to themotherapeutic drugs / 实用医学杂志

Objective Establishment of an osimertinib-resistant PC-9/ZDOR cell line of human non-small cell lung cancer (NSCLC) , and exploration of its drug resistance mechanisms and the sensitivity of themotherapeutic drugs. Methods An osimertinib-resistant PC-9/ZDOR cell line was induced by increasing doses of osimertinib to gefitinib-resistant cells PC-9/ZD. Mutation analysis of EGFR genes was performed by NGS. Cell growth was measured by CCK-8 assay and the sensitivity of chemotherapy was determined via analysis of resistance index (RI).The expression of EGFR and its signal transduction protein was determined by western blot. Results (1) An osimertinib-resistant human NSCLC cell line PC-9/ZDOR was successfully established with resistance index of 44. (2) The evidence from NGS data showed the mutation and amplification of EGFR was eliminated in PC-9/ZDOR cells. (3) The data from Western blot showed that the expression of EGFR and its phosphorylated form protein such as P-AKT and P-ERK was significantly decreased in PC-9/ZDOR cells when compared with those in PC-9/ZD cells (P <0.05). (4) The sensitivity of PC-9/ZDOR cell lines to docetaxel, gemcitabine and paclitaxel was significantly higher than that of PC-9/ZD cell lines (P < 0.05) , while the sensitivity of PC-9/ZDOR cell lines to cisplatin and pemetrexed was similar to the one of PC-9/ZD cell lines (P> 0.05). Conclusions The PC-9/ZDOR cell lines is an osimertinibresistant human NSCLC cell line. Elimination of EGFR gene mutation and/or the decrease of protein expressions of EGFR, p-EGFR, p-ERK and p-AKT maybe serve as the mechanisms of acquired resistance to osimertinib. This osimertinib-resistant cell line, PC-9/ZDOR, showed a elevated level of sensitivity to taxanes and gemcitabine.

Label-free quantitative proteomic analysis of acquired herceptin resistance in gastric cancer cells / 药学学报

This study was designed to explore proteins differentially expressed in HER2 positive gastric cancer N87 cells and N87/R cells with an acquired resistance to herceptin based on label-free quantitative proteomics. The extracted proteins were reduced and alkylated, then digested using filter aided sample preparation (FASP); peptides were separated via small manual reversed phase column, analyzed by LC-MS/MS, and identified with protein database 2.1 search engine. Proteins were quantified by intensity based quantification (IBQ) to search for differential proteins by comparison with relatively quantified proteins. The enrichment and network construction in gene ontology (GO) terms, genes-disease and Wikipathway of differential proteins were established through Web Gestalt. A total of 8 509 proteins were detected, among them, 7 163 proteins were further analyzed by bioinformatics, of which 110 proteins were up-regulated and 70 were down-regulated in N87/R cells. The differential proteins showed a significant difference in cellular component, biological process and molecular function in GO terms, respectively. Genes-disease network analysis indicated the association of these differential proteins with neoplasm metastasis, neoplasm invasiveness and inflammation, etc. Wikipathway enrichment analysis revealed the relevance of several signaling pathways to herceptin resistance, which included IL-2, MAPK/ERK, mTOR, aurora A, Ret, NF-κB, immune-regulatory and metabolic pathway. Western blot showed a significant increase of ERK1/2 activities in N87/R cells compared with N87 cells. Correspondingly, SCH772984, a MAPK/ERK inhibitor, preferentially reduced the viability of N87/R cells. Taken together, our data suggested that the MAPK/ERK signaling pathway is one of the key pathways that mediate herceptin resistance. This study provides the basic information for exploring the mechanisms of acquired resistance to herceptin in gastric cancer cells.

Lack of association between rrl and erm(41) mutations and clarithromycin resistance in Mycobacterium abscessus complex

BACKGROUND Mycobacterium abscessus complex (MABC) includes species with high resistance rates among mycobacterial pathogens. In fact, MABC infections may not respond to clarithromycin treatment, which has historically been very effective against MABC infection. Molecular markers have been proposed to detect both acquired (rrl polymorphisms) and inducible (erm(41) polymorphisms) clarithromycin resistance in MABC isolates. OBJECTIVES This study aimed to evaluate the susceptibility profile and molecular markers of clarithromycin resistance in MABC. METHODS The clarithromycin susceptibility profile was determined by broth microdilution with reads on days 3, 5, 7 and 14. Mutations in the rrl and erm(41) genes were evaluated by polymerase chain reaction (PCR) using specific primers, followed by sequencing. FINDINGS A total of 14 M. abscessus subsp. abscessus isolates and 28 M. abscessus subsp. massiliense isolates were evaluated, and clarithromycin resistance was observed in all isolates for up to three days of incubation. None of the 42 isolates exhibited a point mutation in the rrl gene, while all the isolates had a T28 polymorphism in the erm(41) gene. Moreover, all 28 M. abscessus subsp. massiliense isolates had a deletion in the erm(41) gene. MAIN CONCLUSIONS While all the MABC isolates exhibited acquired clarithromycin resistance, no isolates exhibited a point mutation in the rrl gene in this study. The M. abscessus subsp. massiliense isolates demonstrated clarithromycin resistance, which is an uncommon phenotype. The molecular data for the rrl and erm(41) genes were not consistent with the phenotypic test results of clarithromycin susceptibility, indicating a lack of correlation between molecular clarithromycin resistance markers for both acquired and inducible resistance.

Research advances on EGFR-targeted therapy and acquired resistance in nonsmall cell lung cancer / 中国肿瘤临床

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer. Small molecular drug therapy that targets epidermal growth factor receptor (EGFR) has significantly improved the survival and quality of life of patients with advanced NSCLC. However, almost all of these patients experience drug resistance. Despite research advances, some of the molecular mechanisms un-derlying acquired remain unknown. This review focuses on recent studies on EGFR mutations, clinical trials of EGFR-targeted drugs, and research on the mechanisms and therapies of acquired resistance. Several molecular testings are needed to clarify the mechanism underlying acquired resistance to achieve personalized care of these patients.

Prevalencia de infecciones intrahospitalarias en el Servicio de Clínica Médica del Hospital Regional de Encarnación 2014-2015 / Prevalence of intrahospital infections in the Internal Medicine Service of the Regional Hospital of Encarnación 2014-2015

RESUMEN Introducción: las infecciones asociadas a cuidados de la salud, conocidas también como infecciones nosocomiales (IN), son un problema relevante de salud pública, se asocian con altas tasas de morbilidad y mortalidad, lo que se traduce en un incremento en los días de hospitalización y los costos de atención. Objetivos: determinar los gérmenes intrahospitalarios más frecuentes y su sensibilidad antibiótica en la sala de Clínica Médica del Hospital Regional de Encarnación periodo 2014-2015. Metodología: estudio descriptivo, observacional de corte transversal, prospectivo, de prevalencia y con componente analítico. Resultados: se evaluaron pacientes hospitalizados encontrándose 114 (6%) pacientes con infecciones intrahospitalarias. El perfil epidemiológico se caracterizó por predomino del sexo femenino (53%), con edad media 56,5 ± 22,5 años y una estancia hospitalaria prolongada. Los aislamientos fueron más frecuentes en orina. Las comorbilidades más frecuentes fueron la hipertensión arterial y la diabetes mellitus. El germen más frecuente aislado fue Klebsiella pneumoniae, con una sensibilidad solo a amikacina y cabapenemes, con 64% BLEE(+) y 20% KPC, seguido por Echerichia coli y Staphylococcus aureus con buena sensibilidad a oxacilina. Conclusión: se halló 6% de infecciones intrahospitalarias y el germen más frecuente fue K. pneumoniae

ABSTRACT Introduction: infectious related to health care, also known as nosocomial infections (NI) are an important public health problem, are associated with high rates of morbidity and mortality, resulting in an increase in days of hospitalization and costs. Objectives: to determine the most frequent nosocomial germs and antibiotic sensitivity in a Medical Ward of the Regional Hospital of Encarnación 2014-2015. Methodology: descriptive, observational cross-sectional study with prospective approach, and analytical component. Results: Hospitalized patients were evaluated and were found 114 (6%) patients with nosocomial infections, below the global average. The epidemiological profile, were characterized by predominance of females 53%, aged 56.5 ± 22.5 years. And a prolonged hospital stay. The germs more common commouly isolated were in urine, the more frequent comorbidities were hypertension and diabetes mellitus. The most frequent isolated germ was Klebsiella pneumoniae, with a sensitivity only to amikacin and Cabapenemes, followed by a Escherichia coli and Staphylococcus aureus oxacillin with good sensitivity. Conclusions: 6% of nosocomial infections were found and the more frequent isolated germ was K. pneumoniae

Effect of Cx43 on acquired gefitinib-resistance mechanisms in human NSCLC HCC827 cells / 中国药理学通报

Aim To explore the effect of connexin 43 ( Cx 4 3 ) on acquired gefitinib-resistance in human non small cell lung cancer ( NSCLC ) . Methods HCC827 GR, a gefitinib-resistant ( GR) NSCLC cell lines from their parental cells was established by gradually in-creasing the concentration of gefitinib. Gefitinib effica-cy in HCC827 and HCC827 GR cells was detected by MTT assay. Expression of Cx43 mRNA in HCC827 and HCC827 GR cells was determined by RT-PCR. The protein expressions of Cx43 and phospho-Akt ( p-Akt) in these cells were detected by Western blot. The func-tional gap junction intercellular communication ( GJIC ) was measured by parachute assay. The cellular locali-zation of Cx43 protein was evaluated by immunofluores-cence staining. Results MTT assay showed less ge-fitinib cytotoxicity in HCC827 GR cells than that in their parental cells with IC50 of (10. 84 ± 0. 021) μmol ·L-1 versus (0. 07 ± 0. 019) μmol·L-1 , respective-ly. Moreover, both mRNA and protein expressions of Cx43 in HCC827 GR cells were significantly lower than those in HCC827 cells ( P<0. 05 ) . However, the p-Akt protein in HCC827 GR cells was obviously higher than that in HCC827 cells ( P<0. 05 ) . Furthermore, treatment with LY294002 caused a significant reduced p-Akt expression, but a significant increased Cx43 ex-pression in HCC827 GR cells. Moreover, no detecta-ble GJIC was found in HCC827 and their GR cells with or without RA ( a well-defined GJIC enhancer ) treat-ment. Immunofluorescence staining clearly showed that Cx43 protein accumulated in the cytoplasm of HCC827 and their GR cells. Conclusion The down-regulation of Cx43 expression in cytoplasm of HCC827 GR cells may contribute to the acquired gefitinib resistance in NSCLC cells by GJIC-independent activation of PI3 K/Akt signaling pathway.

Research Progress in Ameliorating EGFR-TKIs Acquired Resistance of Targeted Therapy in Lung Cancer by Traditional Chinese Medicine / 中国中医药信息杂志

Acquired resistance of EGFR-TKIs has become the major limitation of the efficacy of targeted therapy for lung cancer. Lung cancer has been treated by traditional Chinese medicine (TCM) combined with EGFR-TKIs, which originated from clinic. In recent years, reversing research has been conducted based on clinic application to discuss TCM intervening, improving and reversing EGFR-TKIs acquired resistance becoming a novel target for research. This article reviewed mechanism and effects of TCM herbs and compounds’ with the efficacy of clearing away heat and toxic materials, promoting blood circulation to remove blood stasis strengthening the body resistance, and invigorating the circulation of blood, and proposed that the whole regulation and targeted therapy of TCM may carry out synergistic effect and become innovation treatment model for lung cancer.

Role of cancer stem cells in EMT-induced acquired resistance to EGFR-TKIs in NSCLC cells / 实用医学杂志

Objective To explore the role of cancer stem cells in EMT-induced acquired resistance to EGFR-TKIs in NSCLC. Methods The EGFR del E746-A750 mutated human lung adenocarcinoma PC-9 cell line and gefitinib acquired resistance cell line PC-9/AB were used in this study. EMT was assessed by western blotting assay. The sensitivity to gefitinib was tested with CCK8. Flow cytometry for antibody analysis was used to quantify CSCs within the cell lines. Results Compared with PC-9, PC-9/AB underwent EMT and showed no-table resistance to gefitinib (P < 0.01). Compared with PC-9, the proportions of CSCs were much higher in PC-9/AB. Conclusion EMT plays an important role in the acquired resistance to EGFR-TKIs in NSCLC , possibly through the up-regulation of CSCs.

The treatment for acquired drug resistance of clinical characteristics of patients with non-small cell lung cancer / 中国癌症杂志

Background and purpose:Non-small cell lung cancer (NSCLC) patients who have good curative effect on epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) will inevitably acquired drug resistance. It will effect the survival directly. In contrast, few studies have found that EGFR-TKI effectively acquired drug resistance in patients with clinical characteristics. We investigated clinical characteristics of NSCLC patients who experienced acquired drug resistance during geiftinib therapy. Methods:To review the treatment from the beneift of patients with non-small cell lung cancer. All of the data were obtained from Jan. 2007 to Jan. 2014 in Xinjiang tumor hospital. The treatment for failure of acquired drug resistance of clinical manifestations, time to progress (TTP) and post-progression survival (PPS) were retrospectively analyzed. Results:The total collection of 417 patients. Median TTP was 10.2 months (95%CI:9.5-10.9). The TTP of women adenocarcinoma patients who didn’t smoke signiifcantly extended. When acquired drug resistance happened, 63.3%of patients appeared worse symptoms. The progress of the disease is as follows:209 cases (58.4%) from the primary lesion, 137 cases (38.3%) before the transfer, 194 cases (54.2%) of new happened. Patients of epidermal growth factor receptor (EGFR) wild type had more tendencies of symptomatic deterioration and new central nervous system (CNS) transfer than patients of EGFR mutation type. Patients of exon 19 deletion and L858R mutations on the new transfer were different (41.4%vs 6.3%, P=0.02). PPS was 8.9 months (95%CI:7.4-10.4). Smoking history, performance status (PS) score, new CNS lesions and the subsequent chemotherapy is independent factors of PPS. Conclusion:This study suggests that the clinical manifestations of acquired drug resistance according to EGFR mutation status and EGFR mutation genotype may be different. In addition, after the treatment of acquired drug resistance in patients with non-small cell lung cancer, the subsequent clinical beneift from chemotherapy are also associated with PPS.

Induction of Resistance to BRAF Inhibitor Is Associated with the Inability of Spry2 to Inhibit BRAF-V600E Activity in BRAF Mutant Cells

The clinical benefits of oncogenic BRAF inhibitor therapies are limited by the emergence of drug resistance. In this study, we investigated the role of a negative regulator of the MAPK pathway, Spry2, in acquired resistance using BRAF inhibitor-resistant derivatives of the BRAF-V600E melanoma (A375P/Mdr). Real-time RT-PCR analysis indicated that the expression of Spry2 was higher in A375P cells harboring the BRAF V600E mutation compared with wild-type BRAF-bearing cells (SK-MEL-2) that are resistant to BRAF inhibitors. This result suggests the ability of BRAF V600E to evade feedback suppression in cell lines with BRAF V600E mutations despite high Spry2 expression. Most interestingly, Spry2 exhibited strongly reduced expression in A375P/Mdr cells with acquired resistance to BRAF inhibitors. Furthermore, the overexpression of Spry2 partially restored sensitivity to the BRAF inhibitor PLX4720 in two BRAF inhibitor-resistant cells, indicating a positive role for Spry2 in the growth inhibition induced by BRAF inhibitors. On the other hand, long-term treatment with PLX4720 induced pERK reactivation following BRAF inhibition in A375P cells, indicating that negative feedback including Spry2 may be bypassed in BRAF mutant melanoma cells. In addition, the siRNA-mediated knockdown of Raf-1 attenuated the rebound activation of ERK stimulated by PLX4720 in A375P cells, strongly suggesting the positive role of Raf-1 kinase in ERK activation in response to BRAF inhibition. Taken together, these data suggest that RAF signaling may be released from negative feedback inhibition through interacting with Spry2, leading to ERK rebound and, consequently, the induction of acquired resistance to BRAF inhibitors.

Transformation into large-cell neuroendocrine carcinoma associated with acquired resistance to erlotinib in nonsmall cell lung cancer

No abstract available.

Effect of EGFR-TKI retreatment following chemotherapy for ad-vanced non-small cell lung cancer patients who underwent EG-FR-TKI / 中国肿瘤临床

Objective: Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor (EGFR-TKI) compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired re-sistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the in-fluence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least six months on NSCLC pa-tients. Methods:The data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI (gefitinib 250 mg qd or erlotinib 150 mg qd), and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were as-sessed with CT scan. Results:Of the 27 patients who received EGFR–TKI retreatment, 1 (3.7%) patient was observed in complete re-sponse (CR), 8 (29.6%) patients in partial response (PR), 14 (51.9%) patients in stable disease (SD), and 4 (14.8%) patients in progres-sive disease (PD). The disease control rate (DCR) was 85.2%(95%CI=62%-94%). The median progression-free survival (mPFS) was 6 months (95%CI=1-29). Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCR was 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EG-FR-TKI, 0 patient in CR, 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCR was 85.7%, and the mPFS was 9.5 months. Significant difference was found between the 2 groups in progression-free survival but not in response rate or disease control rate. Conclusion:Retreatment of EGFR-TKIs can be considered an option after failure of chemotherapy for patients who were previously controlled by EGFR-TKI treatment.