Background: Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.Methods: A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.Results: Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/ uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).Conclusions: Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.

Non-small cell lung cancer (NSCLC) is one of the most fatal types of cancer with significant mortality and morbidity worldwide. MicroRNAs (miRs) have been confirmed to have positive functions in NSCLC. In the present study, we try to explore the role of miR-758 in proliferation, migration, invasion, and apoptosis of NSCLC cells by regulating high-mobility group box (HMGB) 3 (HMGB3.) NSCLC and adjacent tissues were collected. Reverse transcription quantitative PCR (RT-qPCR) was employed to detect expression of miR-758 and HMGB3 in NSCLC and adjacent tissues, in BEAS-2B cells and NSCLC cell lines. The targetted relationship between miR-758 and HMGB3 was identified by dual luciferase reporter gene assay. The effects of miR-758 on proliferation, migration, invasion, cell cycle, and apoptosis of A549 cells. MiR-758 expression was lower in NSCLC tissues, which was opposite to HMGB3 expression. The results also demonstrated that miR-758 can target HMGB3. The cells transfected with miR-758 mimic had decreased HMGB3 expression, proliferation, migration, and invasion, with more arrested cells in G1 phase and increased apoptosis. Our results supported that the overexpression of miR-758 inhibits proliferation, migration, and invasion, and promotes apoptosis of NSCLC cells by negative regulating HMGB2. The present study may provide a novel target for NSCLC treatment.

Background Small cell lung cancer (SCLC) is one of the deadliest malignancies and accounts for nearly 15% of lung cancers. Previous study had revealed the genomic characterization of SCLC in Western patients. However, little is known about that in Chinese SCLC patients. Methods Formalin‐fixed paraffin‐embedded tumor tissues and matched blood samples from 122 Chinese SCLC patients were collected for next generation sequencing to detect 450 cancer‐related genes. All pathological diagnoses were confirmed by independent pathologists. Results The most frequently altered genes were TP53 (93.4%), RB1 (78.7%), LRP1B (18.9%), KMT2D (15.6%), FAT1 (11.5%), KMT2C (11.5%), SPTA1 (11.5%), STK24 (11.5%), FAM135B (10.7%), and NOTCH1 (10.7%). The gene fusion/rearrangement detection rate was 16.4%, and mostly occurred in chromosomes 7 and 17. The rate of co‐occurring mutations of TP53 and RB1 in these Chinese SCLC patients was 74.6%, and lower than the reported Western patients (90.9%, P = 0.007). The most common gene mutations (83.6%) were found in cell cycle signaling pathway in Chinese SCLC patients. Mutation of Wnt and Notch signaling pathways in the Chinese cohort were lower than Western cohort ( P = 0.0013 and 0.0068). A significant association was found between high tumor mutation burden and mutations involved in FAT1 , TP53 , SPTA1 , KEAP1 , KMT2D , MAGI2 , NOTCH2 , NOTCH3 , FLT1 , KDM6A , and FAT4 . Conclusions In this study, we characterized the genomic alterations profile of Chinese SCLC patients. Compared with westerners, the genetic alterations of Chinese SCLC patients presented different patterns. Our data might provide useful information in targeted therapy and drug development for Chinese SCLC patients.

BackgroundGastric cancer is one of most commonly diagnosed cancers and causes significant mortality worldwide. In this study, the antiproliferative and anticancer effects of Phloretin were evaluated against gastric cancer cell lines.Material/MethodsMTT assay was used to assess the proliferation rate of gastric cancer cells. DAPI and annexin V/PI were used for detection of apoptotic cell death. Cell invasion was investigated by Transwell assays and the expression of the proteins was estimated by immunoblotting.ResultsThe results revealed that Phloretin exerts anticancer effects on all the gastric cancer cell lines used in this study. However, the anticancer effects were more significant (p<0.05) on the AGS cell line. Further, the effect of Phloretin on the viability of normal GES-1 cells was minimal. Apoptosis assays showed that Phloretin triggers apoptotic cell death in AGS gastric cancer cells. Phloretin could also cause the arrest of the AGS gastric cancer cells in the G2/M phase of the cell cycle and suppress their ability to migrate. Western blotting analysis revealed that Phloretin significantly decreased the expression of p-JNK and p-38. However, comparatively lower effects were observed on the expression of JNK and P38.ConclusionsWe showed that Phloretin is an important molecule for the treatment of gastric cancer.