Anlotinib plus icotinib as a potential treatment option for EGFR-mutated advanced non-squamous non-small cell lung cancer with concurrent mutations: final analysis of the prospective phase 2, multicenter ALTER-L004 study.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. METHODS: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. RESULTS: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6-17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5-34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5-18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). CONCLUSIONS: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03736837.

Exosomal miR-27a Derived from Gastric Cancer Cells Regulates the Transformation of Fibroblasts into Cancer-Associated Fibroblasts.

BACKGROUND/AIMS: The malignant biological behavior of gastric cancer(GC) is not only determined by cancer cells alone, but also closely regulated by the microenvironment. Fibroblasts represent a large proportion of the components in the tumor microenvironment, and they promote the development of disease. Currently, accumulating evidence suggests that exosomes can function as intercellular transport systems to relay their contents, especially microRNAs(miRNAs). METHODS: First, we detected the highly-expressed level of miR-27a in exosomes isolated from gastric cancer cells by qRT-PCR. MiR-27a -over-expressed models in vitro and in vivo were established to investigate the transformation of cancer-associated fibroblasts observed by Western blotting, and the malignant behavior of gastric cancer cells using the methods CCK8 and Transwell. Moreover, the downregulation of CSRP2 in fibroblasts was used to evaluate the promotion of malignancy of gastric cancer using the methods CCK8 and Transwell. RESULTS: In this study, we found a marked high level of miR-27a in exosomes derived from GC cells. miR-27a was found to function an oncogene that not only induced the reprogramming of fibroblasts into cancer-associated fibroblasts(CAFs), but also promoted the proliferation, motility and metastasis of cancer cells in vitro and in vivo. Conversely, CAFs with over-expression of miR-27a could pleiotropically increase the malignant behavior of the GC cells. For the first time, we revealed that CSRP2 is a downstream target of miR-27a. CSRP2 downregulation could increase the proliferation and motility of GC cells. CONCLUSION: Thus, this report indicates that miR-27a in exosomes derived from GC cells has a crucial impact on the microenvironment and may be used as a potential therapeutic target in the treatment of GC.

High-mobility group nucleosome-binding protein 1 is a novel clinical biomarker in non-small cell lung cancer.

The involvement of alarmin high-mobility group nucleosome-binding protein 1 (HMGN1) in non-small cell lung cancer (NSCLC) is unknown. To address the presence of HMGN1 in the serum of different stages of NSCLC patients and healthy controls, we enrolled a consecutive sample of adult serum at diagnosis and correlated it with clinicopathologic outcomes. A total of 100 NSCLC patients and 23 healthy volunteers were enrolled from January 2012 through December 2013. Serum HMGN1 levels were determined by enzyme-linked immunosorbent assay (ELISA). Additionally, HMGN1 levels in 50 NSCLC patients with early-stage disease who received curative pneumonectomy were correlated with survivals. Kaplan-Meier plots were used to analyze the data. The patients with NSCLC were characterized by significantly higher serum levels of HMGN1 (0.4585 ± 0.0640 ng/ml) compared to those in healthy controls (0.3578 ± 0.0304 ng/ml). The serum HMGN1 levels were 0.4027 ± 0.0271 ng/ml, 0.4604 ± 0.0328 ng/ml, 0.5408 ± 0.0459 ng/ml, and 0.4213 ± 0.0341 ng/ml in patients with TNM stages I, II, IV, and IV, respectively (p < 0.001). There were significant differences among four groups (p < 0.001). Additionally, a positive correlation between serum HMGN1 and tumor stage was found in local disease, while serum HMGN1 level in metastatic NSCLC patients was significantly decreased. The Kaplan-Meier plots showed that patients with high serum HMGN1 had a poorer overall survival (OS) after curative pneumonectomy than those with low serum HMGN1 (p = 0.019). Inflammation triggered by alarmins plays a role in NSCLC pathogenesis. HMGN1 can serve as a useful clinical parameter for evaluating disease progression and predicting the outcomes for early-stage patients with NSCLC undergoing pneumonectomy.

Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes.

Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFR-mutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of the wild-type patients treated with similar regimens (43 vs. 21%, p = 0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13%, p = 0.715; in the second-/third-line setting 13 vs. 8%, p = 0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFR-mutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/pemetrexed combination chemotherapy.

The role of phosphoglycerate mutase 1 in tumor aerobic glycolysis and its potential therapeutic implications.

A significant characteristic of cancer cell metabolism is the high level of aerobic glycolysis with high glucose consumption and lactate production. Phophoglycerate mutase 1 (PGAM1) is an enzyme that catalyzes the interconversion of 3-phosphoglycerate and 2-phosphoglycerate during glycolysis. It has been reported that this enzyme is commonly upregulated in many human cancers. PGAM1 plays an important role in coordinating glycolysis and anabolic activity to promote cancer cell proliferation. However, the mechanisms under these effects are still poorly understood. This review focuses on the most recent advances in the structure and functions of PGAM1, and PGAM1's role in glycolysis in cancer cells and regulators that modulate PGAM1's effects. Progress in understanding of PGAM1 will provide the rationale to support the development of new hypothesis-driven studies to define PGAM1's potential therapeutic implications for cancer treatment.

MicroRNA-384 radiosensitizes human non-small cell lung cancer by impairing DNA damage response and repair signaling, which is inhibited by NF-κB.

OBJECTIVE: Radiotherapy has achieved remarkable effects in treating non-small cell lung cancer (NSCLC). However, radioresistance remains the major obstacle to achieving good outcomes. This study aims at identifying potential targets for radiosensitizing NSCLC and elucidating the underlying mechanisms. METHODS: Lentivirus-based infection and CRISPR/Cas9 technology were used to modulate the expression of microRNA-384 (miR-384). Cell clonogenic formation assays and a xenograft tumor model were used to analyze radiosensitivity in NSCLC cells. Fluorescence-activated cell sorting was used to assess the cell cycle and cell death. Immunofluorescence staining, Comet assays, and homologous recombination or non-homologous end-joining I-SceI/GFP reporter assays were used to study DNA damage and repair. Western blotting and quantitative real-time polymerase chain reaction were used to identify the targets of miR-384. Chromatin immunoprecipitation and polymerase chain reaction were performed to evaluate upstream regulators of miR-384. RESULTS: MiR-384 was downregulated in NSCLC. Overexpression of miR-384 increased the radiosensitivity of NSCLC cells in vitro and in vivo, whereas knockout of miR-384 led to radioresistance. Upregulation of miR-384 radiosensitized NSCLC cells by decreasing G2/M cell cycle arrest, inhibiting DNA damage repair, and consequently increasing cell death; miR-384 depletion had the opposite effects. Further investigation revealed that ATM, Ku70, and Ku80 were direct targets of miR-384. Moreover, miR-384 was repressed by NF-κB. CONCLUSIONS: MiR-384 is an ionizing radiation-responsive gene repressed by NF-κB. MiR-384 enhances the radiosensitivity of NSCLC cells via targeting ATM, Ku80, and Ku70, which impairs DNA damage repair. Therefore, miR-384 may serve as a novel radiosensitizer for NSCLC.

Is lung involvement a favorable prognostic factor for pancreatic ductal adenocarcinoma with synchronous liver metastases?-A propensity score analysis.

BACKGROUND: For advanced pancreatic cancer, pulmonary metastases (PM) have been considered favorable factors compared to metastases of other sites, but it remains unknown whether the prognosis of patients with synchronous liver and lung metastases is better than that of non-PM. METHODS: Data was derived from a two-decade cohort and included 932 cases of pancreatic adenocarcinoma with synchronous liver metastases (PACLM). Propensity score matching (PSM) was applied to balance 360 selected cases, grouped into PM (n = 90) and non-PM (n = 270). Overall survival (OS) and survival-related factors were analyzed. RESULTS: In PSM-adjusted data, the median OS was 7.3 and 5.8 months, for PM and non-PM, respectively (p = 0.16). Multivariate analysis revealed that male gender, poor performance status, higher hepatic tumor burden, ascites, elevated carbohydrate antigen 19-9, and lactate dehydrogenase were factors of poor survival (p < 0.05). Chemotherapy was the only independent significant factor of favorable prognosis (p < 0.05). CONCLUSION: Although lung involvement was indicated to be a favorable prognostic factor for patients with PACLM in the whole cohort, PM were not associated with better survivals in the subset of cases subjected to PSM adjustment.

Lateral automatic landing guidance law based on risk-state model predictive control.

A lateral automatic carrier landing system (ACLS) control law is proposed for carrier-based aircraft, which could suppress the landing risk and increase the control precision. The nonlinear lateral landing equation is transformed into a polytopic model with a serial of state bounds. The landing risk including approach and arresting risks is proposed, and a Kalman filter is used to integrate both risks to construct the landing risk model. The concept of virtual state deviations is adopted by the output augment, which is estimated by an observer. The risk-state model predictive control (MPC) is established on the basis of the landing risk gradient composed of virtual states and time-varying weights. A compared simulation is tested on a semi-physical platform, which verifies excellent performance of the proposed method.

Reachable Set Estimation for Markovian Jump Neutral-Type Neural Networks With Time-Varying Delays.

The reachable set estimation problem for a class of Markovian jump neutral-type neural networks (MJNTNNs) with bounded disturbances and time-varying delays is tackled in this article. With the aid of the delay partitioning method, a novel stochastic Lyapunov-Krasovskii functional containing triple integral terms is constructed in mode-dependent augmented form. To begin with, transition probabilities of the concerned Markovian jump neural networks (NNs) are considered to be completely known. By employing the integral inequality approach and reciprocally convex combination method, it is proved that all state trajectories which start from the origin by bounded inputs can be constrained by an ellipsoid-like set if a group of linear matrix inequalities (LMIs) is feasible. Then, the free-connection weighting matrix technique is utilized to handle the case of partially known transition probabilities. As byproducts, some sufficient conditions are also obtained to guarantee the stochastic stability of the concerned NNs. The validity of the theoretical analysis is confirmed by numerical simulations.

Dissipativity-Based Consensus Tracking of Singular Multiagent Systems With Switching Topologies and Communication Delays.

This article, based on dissipativity theory, aims to tackle the consensus tracking issue for Lipschitz nonlinear singular multiagent systems (MASs) with switching topologies and communication delays. Rooted at the leader node, a directed spanning tree is assumed to be contained in the union of all possible interaction graphs. Within the framework of topology switching controlled by a Markov chain, communication delays encountered in the data transmission process are reasonably considered to be time-varying and dependent on Markovian jump modes. By using tools from the stochastic Lyapunov functional technique, algebraic graph theory, and strict (Q,S,R)-α -dissipativity analysis, the consensus controller collecting delayed in-neighboring agents' information is designed to ensure stochastic admissibility and strict dissipativity of the resulting consensus error system. The theoretical analysis is validated by numerical simulations.

Expression of ezrin correlates with poor prognosis of nasopharyngeal carcinoma.

A significant proportion of patients with nasopharyngeal carcinoma (NPC) will develop regional relapse or distant metastasis after treatment. So, to find valuable prognostic factors becomes very important. To elucidate the expression of ezrin in NPC and its correlation with patients' clinicopathologic characteristics, time to progression, and overall survival, immunohistochemistry stains for ezrin were applied to 200 tissue specimens of NPC. Ezrin expression had no significant correlation with sex, age, primary tumor stage (T), Epstein-Barr virus (EBV) VCA-IgA antibody, EBV EA-IgA antibody, and EBV DNA copy except primary nodal status (N; p= .032). Increased ezrin expression was significantly related to higher lymph nodal metastatic rate (p< .004). Among ezrin (negative/weak), ezrin (moderate), and ezrin (intense) groups, there was a significant difference for median time to progression (not reached vs. 63.2 months vs. 46 months, P< .001) and median overall survival (100.7 months vs. 80.8 months vs. 70.6 months, P< .001). Ezrin expression status was an independent prognostic factor in multivariate (Cox) analysis. Ezrin, which was significantly correlated to prognosis of disease, may be involved in the tumorigenesis, progression, and invasion of NPC. Thus, our data offer the possibility of future therapeutic targets.

Correlation of genes associated with drug response to prognosis of large cell lung carcinoma.

Platinum-based chemotherapy remains the main treatment of advanced lung cancer. However, platinum resistance has become a major treatment obstacle. Novel therapies, particularly tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) and agents that target vascular endothelial growth factor (VEGF), have improved the treatment. Both chemotherapy and targeted therapy have their molecular mechanisms. This study aimed to determine the mutation, amplification, or expression status and interrelationships of the epidermal growth factor receptor (EGFR), K-Ras proto-oncogene, excision repair cross-complementation group 1 (ERCC1), and VEGF genes as well as their correlations to prognosis of large cell lung carcinoma (LCLC) after EGFR-targeted therapy, chemotherapy, and anti-VEGF therapy. EGFR and K-Ras mutations in 60 specimens of LCLC were detected by direct DNA sequencing. EGFR, ERCC1, and VEGF protein expression was detected by immunohistochemistry (IHC). EGFR gene copy number was detected by fluorescence in situ hybridization (FISH). One (1.7%) patient had an EGFR L858M point mutation in exon 21, 3 (5.0%) had K-Ras mutations, and 10 (19.6%) had EGFR amplification (FISH positive). Positive rates of EGFR, ERCC1, and VEGF proteins were 38.3%, 56.7%, and 70.0%, respectively. EGFR amplification was positively correlated to EGFR protein expression (r = 0.390, P = 0.005). The positive rate of VEGF protein was significantly higher in patients with lymph node metastasis than in those without (84.6% vs. 58.8%, P = 0.046). No significant correlations were observed among the EGFR, K-Ras, ERCC1, and VEGF genes. EGFR gene amplification and the low rate of EGFR mutation suggest that patients with LCLC are likely to obtain little benefit from anti-EGFR therapies.

Differences in Lung Cancer Treatment Preferences Among Oncologists, Patients and Family Members: A Semi-Structured Qualitative Study in China.

BACKGROUND: Cancer treatment decision-making often needs to balance benefits, harms, and costs. This study sought to identify the differences in cancer treatment preference among oncologists, patients and their family members in China. METHODS: A semi-structured face-to-face qualitative interview was conducted among oncologists, patients and their family members recruited in four tertiary hospitals in China. The interview guide was developed based on literature review and expert consultation. Participants were asked to indicate their preferences when making lung cancer treatment decisions. All interviews were audio-taped, transcribed verbatim, and thematic analyzed. The preferences were compared among three groups of participants. RESULTS: A total of 17 participants (5 oncologists, 6 dyads of patients and family members) were interviewed between June and July 2019. Five themes, namely, survival benefit, adverse effect/symptom, treatment process, treatment cost, and the impact on daily life were identified. The oncologists and family members gave highest priority on survival benefit, while the patients are concerned most about treatment cost and quality of life. CONCLUSION: This study reveals different preferences for cancer treatment among oncologists, patients and their family members in China. Education is needed to empower patients and family members and promote share decision-making in this country.

STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven to play important roles in the initiation and progression of various cancers, including NSCLC. In this manuscript, we identified microRNA-135b (miR-135b) as a tumor-promoting miRNA in NSCLC. We found that miR-135b was significantly upregulated and that its upregulation was associated with poor prognosis in NSCLC patients. miR-135b was an independent prognostic factor in NSCLC. Overexpressing miR-135b significantly promoted the aggressiveness of NSCLC, as evidenced by enhanced cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis in vitro and in vivo, and knockdown of miR-135b had the opposite effects. Mechanistically, our results reveal that miR-135b directly targets the 3'-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-κB signaling. Moreover, we found that interleukin-6 (IL-6)/STAT3 could elevate miR-135b levels and that STAT3 directly bound the promoter of miR-135b; thus, these findings highlight a new positive feedback loop of the IL-6/STAT3/miR-135b/NF-κB signaling in NSCLC and suggest that miR-135b could be a potential therapeutic target for NSCLC.

XPO1 inhibition synergizes with PARP1 inhibition in small cell lung cancer by targeting nuclear transport of FOXO3a.

Patient mortality rates have remained stubbornly high for the past decades in small cell lung cancer (SCLC) because of having no standard targeted therapies with confirmed advantages at present. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models but have had unsatisfactory clinical results in SCLC. By RNA-seq and isobaric tags for relative and absolute quantification (ITRAQ), we revealed that PARP1 inhibition led to the relocalization of forkhead box-O3a (FOXO3a) from nuclear to cytoplasm. By performing co-Immunoprecipitation (co-IP) and CRISPR-Cas9-mediated knockout plasmid we showed that FOXO3a was subject to exportin 1 (XPO1)-dependent nuclear export. We demonstrated the effects of the PARP inhibitor BMN673 on apoptosis and DNA damage were markedly enhanced by simultaneous inhibition of XPO1 in vitro. The combination of BMN673 and the XPO1 inhibitor selinexor inhibited primary SCLC cell proliferation in mini-patient-derived xenotransplants (miniPDXs) and markedly inhibited tumor growth without significant toxicity in xenograft models. The efficacy was enhanced for more than 2.5 times, compared to the single agent. Based on these findings, we further designed a novel dual PARP-XPO1 inhibitor and showed its effectiveness in SCLC. In this work, we illustrated that combining a PARP inhibitor with an XPO1 inhibitor is associated with significantly improved efficacy and tolerability. Dual PARP-XPO1 inhibition restored the FOXO3a balance and activity in SCLC. Collectively, targeting PARP1 and XPO1 opens new avenues for therapeutic intervention against SCLC, warranting further investigation in potential clinical trials.

Prognostic and clinicopathological significance of NRF2 expression in non-small cell lung cancer: A meta-analysis.

Nuclear factor erythroid 2-related factor 2 (NRF2) functions as a transcription factor and regulates a wide array of antioxidant and stress-responsive genes. NRF2 has been widely implicated in different types of cancers, but only limited studies concerning the relationship between NRF2 expression and tumour invasion or prognosis in lung cancer. Therefore, we conducted a meta-analysis to determine the prognostic value of NRF2 in patients with non-small cell lung cancer (NSCLC). The relationship between NRF2 expression in NSCLC patients and clinicopathological features was also investigated. Overall survival (OS) and treatment response rate were evaluated using STATA software. Twenty eligible articles with 2530 lung cancer patients were included in this meta-analysis. The results revealed that high expression level of NRF2 was associated with pathologic distant metastasis (odds ratio (OR) = 2.64, 95% confidence interval (CI) 1.62-4.31; P < 0.001), lymph node metastasis (OR = 2.14, 95% CI: 1.53-3.00; P < 0.001), and tumour node metastasis (TNM) stage (OR = 1.95, 95% CI: 1.52-2.49, P < 0.001). High NRF2 expression was associated with low treatment response rate in platinum-based chemotherapy (HR = 0.11, 95% CI 0.02-0.51; P = 0.005). High expression level of NRF2 is predictive for poor overall survival rate (HR = 1.86, 95% CI 1.44-2.41, P < 0.001) and poor progression-free survival (PFS) (HR = 2.27, 95% CI 1.26-4.09, P = 0.006). Compared to patients with a low level of NRF2 expression, patients with high NRF2 expression levels were associated with worse OS and PFS when given the chemotherapy or EGFR-TKI. Together, our meta-analysis results suggest that NRF2 can act as a potential indicator of NSCLC tumour aggressiveness and help the prognosis and design of a better treatment strategy for NSCLC patients.

Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non-EML4-ALK rearrangements detected from cerebrospinal fluid: A case report.

A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211-ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non-small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose-escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK-positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211-ALK in a patient with LM.

Comparison of Clinicopathological Features and Prognosis between ALK Rearrangements and EGFR Mutations in Surgically Resected Early-stage Lung Adenocarcinoma.

BACKGROUND: A number of mutations in key oncogenes have been identified as important for the initiation and maintenance of lung adenocarcinoma (LAC). This study elucidated the prevalence and prognostic significance of mutations in the epidermal growth factor receptor gene (EGFR) and rearrangements in the anaplastic lymphoma kinase gene (ALK) in patients with surgically resected primary LAC. PATIENTS AND METHODS: We retrospectively analyzed 675 consecutive patients who underwent radical resection at a single institution. We concurrently analyzed mutations in EGFR and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) by reverse transcription (RT)-PCR, and investigated ALK rearrangements by immunohistochemistry. LAC with or without various oncogenic mutations was studied for clinicopathological features and their association with disease-free survival (DFS) and overall survival (OS). RESULT: ALK rearrangements and EGFR mutations were detected in 75 and 312 patients, respectively, with coexistence in 5 cases. ALK rearrangements and mutations in EGFR and KRAS were mutually exclusive. Compared with patients with EGFR mutations, ALK rearrangements were more common in younger patients, and those with advanced tumors, lymph node metastases, and higher rates of postoperative adjuvant therapy. Histologically, EGFR mutations were more common than ALK rearrangements in patients with the acinar predominant subtype and the lepidic predominant subtype of LAC, whereas ALK rearrangements were more frequent in the solid predominant subtype with mucin production and invasive mucinous adenocarcinomas. ALK-positive patients had a significantly worse DFS than those with EGFR mutations and wild-type (WT) patients. The mean OS after surgical procedures was significantly longer in EGFR-mutated versus WT patients. No significant differences were found in patients with ALK-positive tumors compared with EGFR-mutated and WT patients. CONCLUSION: Clinicopathological features of LAC with ALK rearrangements differ from those of LAC with EGFR mutations. Patients with ALK rearrangements had a significantly worse DFS than those harboring EGFR mutations. Thus, ALK rearrangements are an adverse prognostic factor in surgically-resected LAC patients, while EGFR mutations are associated with a better prognosis.

Depleting PTOV1 sensitizes non-small cell lung cancer cells to chemotherapy through attenuating cancer stem cell traits.

BACKGROUND: Prostate tumor over expressed gene 1 (PTOV1) has been reported as an oncogene in several human cancers. However, the clinical significance and biological role of PTOV1 remain elusive in non-small cell lung cancer (NSCLC). METHODS: The Cancer Genome Atlas (TCGA) data and NCBI/GEO data mining, western blotting analysis and immunohistochemistry were employed to characterize the expression of PTOV1 in NSCLC cell lines and tissues. The clinical significance of PTOV1 in NSCLC was studied by immunohistochemistry statistical analysis and Kaplan-Meier Plotter database mining. A series of in-vivo and in-vitro assays, including colony formation, CCK-8 assays, flow cytometry, wound healing, trans-well assay, tumor sphere formation, quantitative PCR, gene set enrichment analysis (GSEA), immunostaining and xenografts tumor model, were performed to demonstrate the effects of PTOV1 on chemosensitivity of NSCLC cells and the underlying mechanisms. RESULTS: PTOV1 is overexpressed in NSCLC cell lines and tissues. High PTOV1 level indicates a short survival time and poor response to chemotherapy of NSCLC patients. Depleting PTOV1 increased sensitivity to chemotherapy drugs cisplatin and docetaxel by increasing cell apoptosis, inhibiting cell migration and invasion. Our study verified that depleting PTOV1 attenuated cancer stem cell traits through impairing DKK1/ß-catenin signaling to enhance chemosensitivity of NSCLC cells. CONCLUSION: These results suggest that PTOV1 plays an important role in the development and progression of human NSCLC and PTOV1 may serve as a therapeutic target for NSCLC patients.

WT1-interacting protein inhibits cell proliferation and tumorigenicity in non-small-cell lung cancer via the AKT/FOXO1 axis.

Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide; hence, it is imperative that the mechanisms underlying the malignant properties of lung cancer be uncovered in order to efficiently treat this disease. Increasing evidence has shown that WT1-interacting protein (WTIP) plays important roles both physiologically and pathologically in humans; however, the role of WTIP in cancer is unknown. Here, we investigated the role and mechanism of WTIP in cell proliferation and tumorigenesis of non-small-cell lung cancer (NSCLC). We report that WTIP is a tumor suppressor in human NSCLC. We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation. Downregulation of WTIP significantly correlates with poor prognosis and predicts a shorter overall survival and progression-free survival among NSCLC patients. Moreover, ectopic overexpression of WTIP dramatically inhibits cell proliferation and tumorigenesis in vitro and in vivo; conversely, depletion of WTIP expression shows the opposite effects. Mechanistically, WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. Collectively, the results of the current study indicate that WTIP is an important proliferation-related gene and that WTIP expression may represent a novel prognostic biomarker for NSCLC.