Detection of an EML4-ALK fusion mutation secondary to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer: a case report.

BACKGROUND: For epidermal growth factor receptor-mutant (EGFR-mutant) advanced non-small cell lung cancer (NSCLC) patients, EGFR-tyrosine inhibitors such as gefitinib, erlotinib, and osimertinib, are recommended as the preferred first-line treatment. Unfortunately, relevant drug resistance is often inevitable and for first and second generation EGFR-tyrosine kinase inhibitors (TKIs), drug resistance most commonly (50-60% of cases) occurs at the secondary point mutation T790M. Second-line treatments may include administering the third generation of EGFR-TKIs, such as osimertinib and almonertinib. In a few relevant studies, rearrangement of the anaplastic lymphoma kinase (ALK) gene was detected in patients with T790M mutation after drug resistance to osimertinib re-occurred following administration as a second-line treatment. The studies concluded that ALK rearrangement is a rare but critical drug resistance mechanism for osimertinib. However, to date, it remains unclear whether almonertinib also triggers the same ALK rearrangement. The current case study is the first one detailing the detection of an ALK rearrangement after almonertinib resistance in advanced EGFR-mutant NSCLC, which contributes to the limited body of literature examining ALK rearrangement as a mechanism of resistance to EGFR-TKIs in advanced EGFR-mutant NSCLC. CASE DESCRIPTION: Herein, we present a 35-year-old female patient with EGFR-mutant advanced NSCLC in the last trimester of pregnancy. The patient was administered multiple treatments, including first-line icotinib and second-line almonertinib. According to the next-generation sequencing (NGS) assay after almonertinib resistance, the development of an EML4-ALK fusion mutation was considered to be a potential mechanism of almonertinib resistance. Subsequently, the patient received a combination of almonertinib and crizotinib, and at the last follow-up, the treatment showed a curative effect and then maintained a one-month stable disease. CONCLUSIONS: This case report suggests that ALK rearrangement may be a potential mechanism of almonertinib resistance. The combination of ALK TKI therapy and EGFR TKI may be a viable strategy for almonertinib-resistant NSCLC patients induced by ALK rearrangement.

Efficacy and Safety of Gefitinib Plus Anlotinib for Patients with EGFR Positive Advanced Non-Small-Cell Lung Cancer: A Retrospective Exploratory Study.

Objective: This study was to investigate the efficacy and safety of gefitinib plus anlotinib for patients with EGFR positive advanced non-small cell lung cancer (NSCLC) in a first-line setting. Methods: A total of 36 patients with previously-untreated EGFR positive advanced NSCLC were included in this study retrospectively. All patients were administered with gefitinib plus anlotinib combination therapy. The efficacy of the patients was evaluated with the change of target lesion using imaging evidence according to RECIST 1.1 criteria and all the patients were followed up regularly. Adverse reactions were collected and documented during the combination administration. Univariate analysis according to the baseline characteristic subgroup was implemented using Log rank test and multivariate analysis was adjusted by Cox regression analysis. Results: All the 36 patients included in our study were available for efficacy and safety analysis. Best overall response of the patients during gefitinib plus anlotinib administration suggested that partial response was observed in 30 patients, stable disease was noted in five patients, and progressive disease was found in one patient, which yielded an objective response rate (ORR) of 83.3% (95% CI=67.2-93.6%) and a disease control rate (DCR) of 97.2% (95% CI=85.5-99.9%). Prognostic data indicated that the median progression-free survival (PFS) of the 36 patients with NSCLC was 15.2 months (95% CI=8.15-22.26). Furthermore, the median overall survival (OS) of the 36 patients was 35.9 months (95% CI=22.77-49.03). Additionally, the most common adverse reactions of the patients with NSCLC were diarrhea (63.9%), fatigue (58.3%), hypertension (50.0%), rash (44.4%), and nausea and vomiting (41.7%). Furthermore, ECOG performance status was associated with PFS of gefitinib plus anlotinib combination therapy in baseline characteristic subgroup analysis. Conclusion: Gefitinib plus anlotinib regimen demonstrated encouraging efficacy and an acceptable safety profile for patients with previously untreated EGFR positive NSCLC preliminarily. The conclusion should be validated in prospective clinical trials subsequently.

MicroRNA­145 inhibits migration and induces apoptosis in human non­small cell lung cancer cells through regulation of the EGFR/PI3K/AKT signaling pathway.

In the present study, the therapeutic effects and the underlying molecular mechanisms of microRNA (miR)­145 were investigated in non­small cell lung cancer (NSCLC) cells. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to examine miR­145 expression. An MTT assay and flow cytometry were used to investigate cell proliferation and apoptosis, respectively. The protein expression of Bax, epidermal growth factor receptor (EGFR), phosphatidylinositol 3­kinase (PI3K) and phosphorylated­protein kinase B (AKT) was examined by western blot analysis. miR­145 expression was downregulated in patients with NSCLC who were treated with chemotherapy. The downregulation of miR­145 in A549 cells reduced lactate dehydrogenase (LDH) expression, apoptosis, caspase­3/-9 levels and Bax protein expression, while it increased cell proliferation. Upregulation of miR­145 in A459 cells increased LDH, apoptosis, caspase­3/-9 levels and Bax protein expression, while it inhibited cell proliferation. The EGFR/PI3K/AKT signaling pathway was suppressed by miR­145 upregulation in A549 cells and induced by miR­145 downregulation. The EGFR inhibitor suppressed the EGFR/PI3K/AKT signaling pathway and increased the anticancer effects of miR­145 upregulation in A549 cells. The PI3K inhibitor suppressed the PI3K/AKT signaling pathway and reversed the anticancer effects of miR­145 upregulation in A549 cells. In conclusion, the present study demonstrated that miR­145 regulates the EGFR/PI3K/AKT signaling pathway in patients with NSCLC.

Over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced non-small cell lung cancer cells through PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR.

The present study determined the anticancer activity and its mechanism of microRNA­133b on cell proliferation of cisplatin-induced non-small cell lung cancer cells. The expression of microRNA-133b cisplatin­induced non-small cell lung cancer (NSCLC) tissue was lower than that of para-carcinoma tissue in patients. Overall survival of higher expression in cisplatin-induced NSCLC patients was higher than that of lower expression in cisplatin­induced NSCLC patients. Over-regulation of microRNA-133b inhibited cell proliferation and LDH activity, induced apoptosis and caspase-3 activity, suppressed the protein expression of EGFR, PI3K, p-Akt, p-JAK2 and p-STAT3, decreased cyclin D1 and increased Bax protein expression in cisplatin­induced A549 cells. EGFR inhibitor (lapatinib) suppressed EGFR protein expression, inhibited cell proliferation and LDH activity, and induced apoptosis and caspase-3 activity in cisplatin-induced A549 cells by over-regulation of microRNA-133b. When EGFR protein expression was suppressed, PI3K, p-Akt, p-JAK2 and p-STAT3, decreased cyclin D1 and increased Bax protein expression in cisplatin-induced A549 cells by over-regulation of microRNA-133b. Altogether, our results indicated that over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced NSCLC by PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR.

[Effect of temperature and applied voltage on the recombination efficiency in double layer organic light emitting diodes].

In this paper, the theoretical model of recombination was presented and the effect of temperature and applied voltage on the recombination efficiency was investigated in double layer organic light-emitting diodes: ITO/PPV/PBD/Ca. At lower applied voltage, two peaks have been observed in the curve of recombination efficiency vs. temperature. With increasing voltage, the two peaks shifted toward each other, and at voltage around 9 V the two peaks converged. These phenomena were attributed to the excited deep and shallow trap levels and the change of recombination zone. In the Frenkel exciton model, the temperature dependence of the quantum efficiency depended on the carriers mobilities and carriers densities. The carriers mobilities increased with decreasing temperature, while the carriers densities decreased with decreasing temperature. Therefore, a peak in the curve of quantum efficiency vs. temperature was expected in the model. The high-temperature peak originated due to radiative recombination of the deep trap levels, but the low-temperature peak due to shallow ones. On the other hand, as the voltage increased, the recombination zone would be changed, which had some effects on the recombination efficiency. Some experiments proved our theoretical prediction.

[Influences of transport layers barriers on recombination efficiency in bilayer organic devices].

Based on the physical processes of carriers transport and recombination, a multi-barriers model for carriers transport and recombination in bilayer organic devices is present. The influences of applied bias and thin films (transport layers) barriers on carriers recombination and its efficiency are calculated and discussed. In bilayer organic devices the charge density inside the sample is controlled by interfacial charge accuulation. Interfacial charge accumulation enhances the field in the cell compartment adjacent to the contact at which minority carrier injected. This gives rise to enhanced minority carriers injection and explains why efficient bilayer organic devices can be fabricated. For appropriate values of anodic and cathodic zone energy barriers, a greater recombination efficiency can be acquired. The theory from this model reasonably explained the experimental phenomens, and it proved that the field can control the carriers recombination regions.

[Mechanism and fluorescence spectra of 5,6,11,12-tetraphenyl-tetracene doped 8-hydroxyquinoline system].

The PL and EL spectra of 5,6,11,12-tetraphenyl-tetracene doped 8-hydroxyquinoline are measured. It is found that Alq is host emitter when dopant concentration is low, and a discrete level is introduced by doping Rubrene (guest emitter) in Alq energy gap. As increasing Rubrene concentration, Rubrene is host emitter but Alq becomes guest emitter. Because overlap between absorption spectrum of Rubrene and emission spectrum of Alq is greater, the energy transfer and charge transfer between host emitter and guest emitter are occurred in PL of doping Alq thin film. As conductive band (LUMO) of Rubrene is much lower than that of Alq, and their valence bands (HOMO) are about the same, and electron concentration of conductive band of Rubrene is much greater than that of Alq, the rate of recombination between the electrons in conductive band and holes in valence band of Rubrene is much greater than in Alq, so EL is mainly emission of Rubrene.

[Defect modes in one-dimensional comblike photonic crystals].

The photonic band structures and the effect of defect states on photonic band gap in a comblike waveguide geometry which were made of dangling side branches grafted periodically along an infinite monomode waveguide were investigated in this paper. It was discovered that the photonic forbidden bands originates from both the periodicity of the system and the resonance states of the grafted branches. By removing or inserting some defect branches in the star waveguide of finite number of grafted branches, the localized states appear in the transmission spectrum as very narrow peaks. The behavior of the localized states was analyzed as the functions of the length, the position and the number of the defective branches.