Therapy For Non-small Cell Lung Cancer Research Articles

Jaceosidin inhibits the progression and metastasis of NSCLC by regulating miR-34c-3p/Integrin α2β1 axis

Non-coding RNAs are crucial for cancer progression, among which miR-34c-3p has been demonstrated to be a tumor suppressor in non-small cell lung cancer (NSCLC). In this study, we attempt to identify flavonoids that can up-regulate miR-34c-3p expression, evaluate the anticancer activity of the flavonoids and explore its underlying mechanism in NSCLC cells. Six flavonoids were screened by RT-qPCR and we found that jaceosidin significantly increased miR-34c-3p expression in A549 cells. We found that jaceosidin inhibited the proliferation, migration and invasion of A549 and H1975 cells in a dose-relevant manner, indicated by cell counting kit (CCK-8) assay, wound healing assay, transwell assay and EdU assay, we observed that jaceosidin inhibited the proliferation, migration and invasion of A549 and H1975 cells in a dose-relevant manner. Further research suggested that miR-34c-3p bound to the transcriptome of integrin α2β1 and then inhibited its expression, leading to the inhibitory effect on the migration and invasion of NSCLC. Our study sheds some light on anti-tumor of jaceosidin and provides a potential lead compound for NSCLC therapy.

'Targeting' Improved Outcomes with Antibody-Drug Conjugates in Non-Small Cell Lung Cancer-An Updated Review.

Antibody-Drug conjugates (ADCs) are a relatively new class of drugs with a promise to improve the outcomes in specific cancers. By delivering the cytotoxic agent to tumor cells expressing specific antigens, ADCs achieve a better therapeutic index and more potency. ADCs have been approved for several hematological and solid malignancies, including breast, urothelial and gastric carcinoma. Recently, trastuzumab deruxtecan (TDXd) was the first ADC approved for previously treated metastatic HER2-mutant non-small cell lung cancer (NSCLC). Many promising ADCs are in the pipeline for clinical development in non-small cell lung cancer, including sacituzumab govitecan, patritumab deruxtecan, datopotamab deruxtecan and tusamitamab ravtansine. There is a hope that these drugs would cater to the unmet need of specific patient populations, including patients with currently untargetable mutations. We hope these drugs, e.g., TROP2 targeted ADCs, will also give more options for therapy in NSCLC to improve outcomes for patients. In this comprehensive review, we will be discussing the recent evidence including targets, efficacy and the safety of newer ADC candidates in NSCLC. We will also briefly discuss the specific toxicities, novel biomarkers, overcoming resistance mechanisms, challenges and the way forward, as these new ADCs and combinations find a way into the clinical practice.

The toxicity associated with combining immune check point inhibitors with tyrosine kinase inhibitors in patients with non-small cell lung cancer.

Latest advances in non-small cell lung cancer (NSCLC) therapies have revolutionized the treatment regimens utilized for NSCLCs with or without a driver mutation. Molecular targeted treatments such as tyrosine kinase inhibitors (TKIs) are utilized to prevent tumor progression and improve survival. Despite the great benefit of immunotherapy in NSCLC tumors with no driver mutation, the use of immune checkpoint inhibitors (ICIs) in NSCLC tumors harboring a driver mutation has been under debate. Furthermore, several trials have been conducted investigating the use of these therapies with TKIs. A few trials were halted due to growing concerns of increased toxicity with the combination of TKI and immunotherapy. The adverse events ranged from low grade dermatologic complaints to fatal interstitial lung diseases. These toxicities occur with both concurrent and sequential administration of treatment. Thus, recommendations for the safest method of combination treatment have not yet been described. This review paper discusses recent views on combination treatment, previous clinical trials reporting grade 3-4 toxicities, and guidelines for a safe timeline of administration of treatment based on past evidence.

Treatment of lorlatinib induced hypercholesterolemia with PCSK9 inhibitors; A new solution to an emerging need in non-small cell lung cancer therapy

Lorlatinib is a third generation ALK inhibitor used in the treatment of non-small cell lung cancer. Lorlatinib invariably causes hypercholesteremia, though most patients respond to statin therapy.

Abstract 3472: A tumor draining lymph node CD8 T cell memory response is pivotal for a decrease in recurrence after neoadjuvant anti PD-1 therapy for NSCLC

Abstract Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Even at early stages, death rates remain disproportionately high due to metastatic recurrence. Recently, blockade of the PD-1/PD-L1 axis has shown impressive increases in recurrence-free survival in a subset of patients. While efforts to decrease relapse have focused on decreasing residual micrometastatic disease at the time of definitive treatment, PD-1 directed therapy may allow for an adaptive immune response and the establishment of anti-tumor immunosurveillance. Building on results from a clinically relevant murine model of metastatic relapse after tumor resection and robust assays on systematically characterized tumor, lymph node and blood samples of early-stage lung cancer patients, we posit that immunologic CD8 T cell memory may be a primary mechanism of metastatic protection. Methods: We utilized a syngeneic murine model of metastatic lung adenocarcinoma (344SQ) after resection of tumor, tumor draining lymph node (tdLN) and non-draining lymph nodes (ndLN). Using bioluminescent imaging (BLI) and flow cytometric analysis we monitored T cell kinetics and anti-tumor activity after administration of anti-PD-1 antibody and/or KD033, a fusion antibody combining a high affinity anti-PD-L1 IgG1 antibody with an IL-15Rα sushi binding domain. Tumor/tdLN and ndLN T cells were characterized for PD-1/TCF-1/CD62L/CD44/CXCR5 memory phenotypes. In parallel, we analyzed resected tumor, tdLN and ndLN from early-stage NSCLC patients. Results: tdLN from murine models and early-stage patients maintain robust PD-1+ CXCR5+ CD8 T cell memory phenotypes not significantly found in the primary tumor, ndLN and peripheral blood. Neoadjuvant treatment with PD-1 blockade alone had a heterogenous response, with robust proliferation of T cell central and stem cell memory populations (CM & SCM) at the tdLN in responders compared to non-responders (p<0.05). Combination therapy with IL-15Rα agonist (KD033) potentiated diverse PD-1+ CXCR5+ CD8 stem cell like memory subsets in the tdLN and subsequent response at the primary tumor (100%) as well as displayed superior protection against metastatic recurrence up to 200 days compared to PD-1 inhibition or KD033 alone (median survival undetermined vs. 120d, 161d respectively p<0.05). Removal of tdLN or blockade of lymph node migration with FTY720 prior to therapy decreased a population of SCM and CM CD8 T cells found in the primary tumor, decreased primary tumor response and altered systemic memory subpopulations in the ndLN (p<0.05). Conclusions: Our data strongly points to a T cell memory response within the tumor draining lymph node as a possible driver of protection from systemic cancer recurrence, laying the groundwork for a new therapeutic strategy aimed at establishing CD8 immunosurveillance for protection from cancer recurrence. Citation Format: Tatiana Delgado Cruz, Geoffrey J. Markowitz, Mitchell Martin, Arshdeep Singh, Shelley Yang Bai, Nasser Altorki, Timothy McGraw, Vivek Mittal, Jonathan Villena-Vargas. A tumor draining lymph node CD8 T cell memory response is pivotal for a decrease in recurrence after neoadjuvant anti PD-1 therapy for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3472.

Abstract 2009: Gemcitabine-loaded EGFR aptamer for targeted therapy of lung cancer

Abstract Lung cancer is the leading cause of cancer-related death in the world and non-small cell lung cancer (NSCLC) is the most common types of the lung cancer. Epidermal growth factor receptor (EGFR) is an attractive therapeutic target due to its high expression in NSCLC. Gemcitabine (Gem) has shown antitumor activity against many kinds of solid tumors, including NSCLC. Aptamers emerged as promising drug delivery vehicles because of their high binding affinity for the target molecules. The objective of this study was to develop the aptamer-drug conjugates using the EGFR-specific aptamer. EGFR aptamers selected by the SELEX process and gemcitabine was internally incorporated into the EGFR aptamer. In vitro binding affinity of EGFR and Gem-loaded EGFR aptamer was evaluated on EGFR-positive A549, H460, H1299 cell lines, as well as EGFR-negative H522 cells using confocal microscopy. To determine whether the Gem-loaded EGFR aptamer was effectively internalized, Z-stack images were acquired after 1 hr incubation of Cy5-conjugated EGFR aptamer at 37°C. The ex vivo biodistribution of Cy7-conjugated EGFR aptamer was investigated in NSCLC xenograft nude mice. To confirm the antiproliferative effects of Gem-loaded EGFR aptamer, the MTT cell proliferation assay was carried out in NSCLC cells. In the confocal image of EGFR-positive cells, Gem-loaded EGFR aptamers were selectively bound to the cell surface, while no aptamer binding was observed in H522 cells. Z-stack imaging showed that internalized Gem-loaded EGFR aptamer accumulated in EGFR-positive cells. The ex vivo biodistribution data showed that the Gem-loaded EGFR aptamer exhibited higher binding in EGFR-positive A549 tumors than scramble EGFR aptamer. A549 cells showed significant reduction in proliferation following treatment with Gem-loaded EGFR aptamer. Our results indicated that Gem-loaded EGFR aptamer has a potential therapeutic agent in EGFR-positive NSCLC therapy. Citation Format: Jun Young Park, Ye Lim Cho, Ju Ri Chae, Won Jun Kang. Gemcitabine-loaded EGFR aptamer for targeted therapy of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2009.

Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC.

Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

Genomic landscape and efficacy of HER2-targeted therapy in patients with HER2-mutant non-small cell lung cancer.

HER2-targeted therapy provides survival benefits to HER2-mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of treatment-naïve HER2-positive NSCLC, as well as the efficacy of and resistance to HER2-targeted therapy in HER2-altered NSCLC, could promote further improvement of HER2 targeted therapy. HER2-altered NSCLC patients was retrospectively included and their genomic profiles were performed by next-generation sequencing. The clinical outcomes included overall response rate, disease control rate and progression-free survival. Among 176 treatment-naïve patients with HER2 alterations, 64.8% harbored HER2 mutations with/without HER2 amplification, and 35.2% carried HER2 amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with HER2 oncogenic mutations showed a higher prevalence of TP53 mutations and a higher tumor mutation burden. However, this correlation was not found in patients with HER2 amplification only. Twenty-one patients with HER2 alterations treated with pyrotinib or afatinib were retrospectively enrolled. Pyrotinib yielded a longer median progression-free survival than afatinib (5.9 [95% CI, 3.8-13.0] vs. 4.0 months [95% CI, 1.9-6.3], P = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified de novo HER2 copy number gain and G518W mutation, as well as mutations involving DNA damage repair signaling, SWI-SNF complex, and epigenetic regulations as potential resistance mechanisms. HER2-mutant NSCLC had different molecular features from HER2-amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in HER2-altered NSCLC, although larger cohorts are warranted to validate it. HER2-dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.

Precision targeted therapy for EGFR mutation‐positive NSCLC: Dilemmas and coping strategies

The most common driver gene mutation in patients with non-small-cell lung cancer (NSCLC) is an epidermal growth factor receptor (EGFR) mutation. With the introduction of EGFR-tyrosine kinase inhibitors, the treatment prospects and prognosis of NSCLC patients with EGFR-sensitive mutations have significantly improved. Nonetheless, therapies targeting NSCLC are still associated with a risk of primary or secondary nonclassical drug resistance mutations. In recent years, the research and methodology have led to the continuous discovery of new drugs and drug resistance targets. These explorations have also resulted in continuously discovering new drugs. Consequently, rapid advancements have been made to overcome NSCLC drug resistance. This study aimed to review the current dilemma of targeted therapy for EGFR mutation-positive NSCLC and the coping strategies for these difficulties.

A molecular beacon-assisted nanotheranostic agent for real-time detection and effective combined management of acquired resistance to EGFR-TKIs

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitably developed in non-small cell lung cancer (NSCLC) and the major cause of resistance to first-generation EGFR-TKIs is the T790M secondary mutation. Real-time detection of the acquired T790M mutation to avoid futile treatment and timely adjust the therapeutic interventions remains a great challenge. Molecular beacon (MB) could achieve real-time detection of point mutation and the fluorophores located at the terminal of MB could be activated for photodynamic therapy (PDT). Herein, a multifunctional nanoplatform CQEM based on erlotinib and tertiary amine dual-fabricated chitosan (CQE) loaded with cyanine dyes-labeled MB was prepared for simultaneous detection of the degree of T790M mutation in real-time and reversal of the resistance by PDT. CQE could protect MB against DNase I digestion and CQEM could achieve real-time sensing of T790M mutation during the course of EGFR-TKI treatments. With 808 nm laser irradiation, CQEM showed substantial therapeutic efficiency and could overcome the acquired resistance by the synergism of targeted molecular therapy and dual-cyanine dyes-mediated PDT. Thus, the CQEM nanoplatform could be an auspicious tool for individualized accurate therapy of NSCLC by real-time detection and management of the efficacy of EGFR-TKIs.

Pretherapy investigations using highly robust visualized biomarkers from CT imaging by multiple machine-learning techniques toward its prognosis prediction for ALK-inhibitor therapy in NSCLC: a feasibility study.

Molecularly targeted therapy has revolutionized the therapeutic landscape and is emerging as the first-line treatment option for ALK-rearranged non-small-cell lung cancer (NSCLC). In this study, the highly informative and robust biomarkers based on pre-treatment CT images and clinicopathologic features will be developed and validated to predict the prognosis for ALK-inhibitor therapy in NSCLC patients. A total of 161 ALK-positive NSCLC patients treated with ALK inhibitors were retrospectively collected as training, validation and test sets from multi-center institutions. Cox proportional hazard regression (CPH) penalized by LASSO and random survival forest (RSF) coupled with recursive feature elimination (RFE) were used for radiomics and clinical features identification and model construction. An overlapping post-processing method was extra added to training process to investigate the stronger biomarker on the whole set. 123 of the collected cases progressed after a median follow-up of 15.5months (IQR, 8.3-25.3). The T and M staging, pericardial effusion, age and ALK inhibitor-alectinib were determined as significant predictors in the survival analysis. Furthermore, we visualized the finally retained 4 radiomics feature. The RSF models built from overlapping-processed clinical and radiomics features respectively reached the maximum C-index of 0.68 and 0.75,but the combination of them,radioclinical signature, improved the score to 0.78. The model on the validation and external test datasets yielded the C-index of 0.73 and 0.79, with the iAUC of 0.76 and 0.83, the IBS of 0.119 and 0.112. With respect to a simple selection strategy of overlapping optimal radiomics and clinical features from different survival models may promote better progression-free survival(PFS) prediction than conventional survival analysis, which provides a potential method for guiding personalized pre-treatment options of NSCLC.

New therapies in non-small cell lung cancer with EGFR exon 20 insertion mutations.

Patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations have a poor prognosis and few therapeutic alternatives. We conducted a review of scientific evidence about therapies in NSCLC with EGFR exon 20 insertion mutations. A systematic review in PubMed® database was performed up to November 19, 2022. Clinical trials (CTs) about treatments of patients diagnosed with advanced or metastatic NSCLC harbouring EGFR exon 20 insertions who had previously received platinum-based chemotherapy were selected. CTs with a sample size of less than 10 patients were discarded. Efficacy results were used to determine the most interesting drugs. Subsequently, a more exhaustive analysis of the design of the CTs and safety of the most interesting schemes was conducted. Comparisons were attempted to develop. A total of 40 records were found in the systematic search. Twelve selected CTs included the following therapies: poziotinib, osimertinib, pertuzumab-trastuzumab-docetaxel scheme, mobocertinib, amivantamab, erlotinib-onalespib regimen, luminespib, ado-trastuzumab emtansine and dacomitinib. Mobocertinib, amivantamab and poziotinib were determined as the most interesting treatments according to efficacy data. Gastrointestinal and dermatological adverse reactions were relevant in these regimens. All CTs presented a non-randomised design. No reliable comparisons could be developed. The efficacy of mobocertinib, amivantamab and poziotinib in NSCLC with EGFR exon 20 insertion mutations is promising. However, therapies were assessed in single-arm CTs with low-quality evidence. Comparative studies with more extensive patient follow-up, larger sample size and better design are needed to reliably quantify the effect of these drugs.

STAT3 silencing by an aptamer-based strategy hampers the crosstalk between NSCLC cells and cancer-associated fibroblasts

The identification of new effective therapeutic options for non-small-cell lung cancer (NSCLC) represents a crucial challenge in oncology. Recent studies indicate that cancer-associated fibroblasts (CAFs) participate in tumor progression by establishing a favorable microenvironment that promotes cancer progression. Therefore, the development of strategies inhibiting the interplay between CAFs and cancer cells is considered a winning approach for the development of effective anti-cancer drugs. Among other factors, the signal transducer and activator of transcription-3 (STAT3) has been reported as a key mediator of CAF oncogenic actions, representing a promising therapeutic target. Here, we applied an aptamer-based conjugate (named Gint4.T-STAT3), containing a STAT3 siRNA linked to an aptamer binding and inhibiting the platelet-derived growth factor receptor (PDGFR)β, to obtain STAT3-specific silencing and interfere with CAF pro-tumorigenic functions. We demonstrated that this molecule effectively delivers the STAT3 siRNA in NSCLC cells, and blocks CAF-induced cancer cell growth and migration and reduced spheroid dimension. In addition, we found that Gint4.T-STAT3 alters CAF phenotype, thus functioning as a double-acting molecule able to inhibit the entire tumor bulk. Our data provide a proof of principle for the targeting of CAF pro-tumor functions through an aptamer-based drug, and can open innovative horizons in NSCLC therapy.

Comparison of Survival Outcomes of Single- and Five-Fraction Schedules of Stereotactic Body Radiation Therapy for Early-Stage Central or Peripheral NSCLC

The treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) frequently involves different fractionation schemes for peripheral and central tumors due to concerns with toxicity. We performed an observational cohort study to determine survival outcomes for patients with peripheral and central NSCLC treated with SBRT. A single-institutional database of patients with early-stage NSCLC treated with SBRT from September 2008 to December 2018 was evaluated. Outcomes were progression-free survival (PFS), overall survival (OS), local failure (LF), nodal failure (NF), and distant failure (DF). Cox multivariable analysis (MVA), Kaplan-Meier plotting, Fine-Gray competing risk MVA, and propensity score matching were performed. A total of 265 patients were included with a median follow-up of 44.2 months. There were 191 (72%) and 74 (28%) patients with peripheral and central tumors treated with single-fraction SBRT to a dose of 27 Gy and five-fraction SBRT to a dose of 50 Gy, respectively. On Cox MVA, there was no difference in OS (adjusted hazards ratio (aHR) of 1.04, 95% CI of 0.74-1.46) or PFS (aHR of 1.05, 95% CI of 0.76-1.45). On Fine-Gray competing risk MVA, there were no differences in LF, NF, or DF. Propensity matching confirmed these findings. The survival outcomes of patients treated with SBRT for early-stage NSCLC were equivalent for central and peripheral tumors.

Raddeanin A promotes autophagy-induced apoptosis by inactivating PI3K/AKT/mTOR pathway in lung adenocarcinoma cells.

Non-small-cell lung cancer (NSCLC) is the most common cancer in the world. Previous studies have shown that Raddeanin A (RA) exhibited distinct antitumor properties in gastric and colon cancer. This study aimed to investigate the pharmacological actions and intrinsic mechanisms of RA in NSCLC. Through the application of network pharmacology, the potential targets of RA for NSCLC therapy such as SRC, MAPK1, and STAT3 were excavated. Enrichment analyses showed that these targets were concerned with the regulation of cell death, regulation of MAPK cascade, Ras signaling pathway, and PI3K/AKT signaling pathway. Meanwhile, 13 targets of RA were identified as autophagy-related genes. Our experiment data showed that RA effectively inhibited proliferation and induced apoptosis in lung cancer cells A549. We also found that RA could induce autophagy simultaneously. Furthermore, the autophagy induced by RA had a synergistic effect with apoptosis and contributed to cell death. Additionally, RA could downregulate the activity of the PI3K/AKT/mTOR pathway. Generally, our results indicated the antitumor effect and underlying mechanisms of RA on apoptosis and autophagy in A549 cells, suggesting that RA could be used as an effective antineoplastic agent.

Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review).

The Warburg effect indicates that cancer cells survive through glycolysis under aerobic conditions; as such, the topic of cancer metabolism has aroused interest. It is requisite to further explore cancer metabolism, as it helps to simultaneously explain the process of carcinogenesis and guide therapy. The flexible metabolism of cancer cells, which is the result of metabolic reprogramming, can meet the basic needs of cells, even in a nutrition-deficient environment. Glutamine is the most abundant non-essential amino acid in the circulation, and along with glucose, comprise the two basic nutrients of cancer cell metabolism. Glutamine is crucial in non-small cell lung cancer (NSCLC) cells and serves an important role in supporting cell growth, activating signal transduction and maintaining redox homeostasis. In this perspective, the present review aims to provide a new therapeutic strategy of NSCLC through inhibiting the metabolism of glutamine. This review not only summarizes the significance of glutamine metabolism in NSCLC cells, but also enumerates traditional glutamine inhibitors along with new targets. It also puts forward the concept of combination therapy and patient stratification with the aim of comprehensively showing the effect and prospect of targeted glutamine metabolism in NSCLC therapy. This review was completed by searching for keywords including 'glutamine', 'NSCLC' and 'therapy' on PubMed, and screening out articles.

Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments.

Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.

CircRNA OXCT1 promotes the malignant progression and glutamine metabolism of non-small cell lung cancer by absorbing miR-516b-5p and upregulating SLC1A5

ABSTRACT Previous study has demonstrated the high expression of circular RNA 3-oxoacid CoA-transferase 1 (circ-OXCT1) in lung adenocarcinoma tumor tissues. However, the role and possible mechanism of circ-OXCT1 in non-small cell lung cancer (NSCLC) progression was unclear.Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) staining assay were performed to detect the expression of circ-OXCT1, microRNA-516b-5p (miR-516b-5p), solute carrier family 1 member 5 (SLC1A5) and other indicated protein markers. Cell proliferation was measured by Cell counting kit 8 (CCK8), colony formation and 5-Ethynyl-2’-deoxyuridine (EdU) assays. Flow cytometry was employed to detect the rate of apoptotic cells. Cell migration and invasion were measured using transwell assay. The relative glutamine uptake and α-ketoglutarate (α-KG) production was determined using commercial kits. Interaction between miR-516b-5p and circ-OXCT1 or SLC1A5 was predicted by bioinformatics analysis and confirmed via luciferase reporter and RNA immunoprecipitation (RIP) assays. In vivo assay was implemented to demonstrate the effect of circ-OXCT1 in tumor growth.Circ-OXCT1 and SLC1A5 were upregulated and miR-516b-5p was downregulated in NSCLC tissues and cells. Functional experiments revealed that circ-OXCT1 silencing suppressed cell proliferation, migration and invasion, but promoted cell apoptosis in vitro. Circ-OXCT1 knockdown repressed tumor formation in vivo. Besides, miR-516b-5p was a target of circ-OXCT1, and miR-516b-5p inhibitor could relieve circ-OXCT1 absence-mediated effects in NSCLC cells. SLC1A5 was identified as a target of miR-516b-5p. Circ-OXCT1 promoted SLC1A5 expression by target binding with miR-516b-5p.Circ-OXCT1 facilitated NSCLC progression via miR-516b-5p-dependent regulation of SLC1A5, which provided a possible circRNA-targeted therapy for NSCLC.

Molecular residual disease: A new clue for individualized approach in non‐small cell lung cancer

AbstractThe prognostic value of molecular residual disease (MRD) in non‐small cell lung cancer (NSCLC) cases using high‐depth circulating tumor DNA (ctDNA) sequencing has been well documented. The utility of MRD to direct individualized therapy has increasingly emerged in the clinical trial design of solid tumors, such as escalation or de‐escalation of adjuvant therapy based on MRD. And the efficiency of MRD assay is a key determinant to the success of clinical trials, especially the limitation of detection and predictive value. Here, we review the progress made in evaluating the clinical validity of ctDNA‐MRD test and provide insight into exploiting these developments to future clinical scenarios for improving the individualized therapy of NSCLC.

Interpretation of expert consensus on treatment for stage III non‐small cell lung cancer

Interpretation of expert consensus on treatment for stage III non‐small cell lung cancer