Therapy For Non-small Cell Lung Cancer Research Articles

Pathologic response and safety to neoadjuvant PD-1 inhibitors and chemotherapy in resectable squamous non-small-cell Lung cancer.

BackgroundSeveral randomized studies have shown that the combination of programmed cell death 1 (PD-1) inhibitor and chemotherapy is efficacious as a treatment for advanced non-small-cell lung cancer (NSCLC). However, in the neoadjuvant setting, there is scarce evidence of the effectiveness and safety of the combinations in squamous NSCLC. We conducted a retrospective study to evaluate neoadjuvant PD-1 inhibitor plus chemotherapy in resectable squamous NSCLC.MethodsPatients from Beijing Chest Hospital, Capital Medical University, between October 2019 and October 2021, treated with PD-1 inhibitors and chemotherapy for resectable squamous NSCLC were retrospectively studied. The primary objectives were to assess the pathological tumor response and safety of neoadjuvant PD-1 inhibitors and chemotherapy.Results63 patients with resectable squamous NSCLC stage IIA-IIIB were included. Two to four cycles of PD-1 inhibitors (37 cases with camrelizumab, 11 cases with toripalimab, 8 cases with tislelizumab, and 7 cases with sintilimab) and chemotherapy were administered prior to surgery. 42 patients (66.7%) achieved a major pathologic response (MPR), including 25 (39.7%) with a pathologic complete response (pCR). Twenty-one patients (33.3%) experienced grade 3 neoadjuvant treatment-related adverse events (TRAEs), and no patient had grade 4 or 5 TRAE.ConclusionNeoadjuvant PD-1 inhibitors and chemotherapy are feasible therapies for resectable squamous NSCLC. It was associated with a 66.7% MPR rate, 39.7% pCR rate, and tolerable toxicity.

Biomarker-Targeted Therapies in Non-Small Cell Lung Cancer: Current Status and Perspectives.

Non-small-cell lung cancer (NSCLC) is one of the most common malignancies and the leading causes of cancer-related death worldwide. Despite many therapeutic advances in the past decade, NSCLC remains an incurable disease for the majority of patients. Molecular targeted therapies and immunotherapies have significantly improved the prognosis of NSCLC. However, the vast majority of advanced NSCLC develop resistance to current therapies and eventually progress. In this review, we discuss current and potential therapies for NSCLC, focusing on targeted therapies and immunotherapies. We highlight the future role of metabolic therapies and combination therapies in NSCLC.

Therapeutic targeting of glutamate dehydrogenase 1 that links metabolic reprogramming and Snail-mediated epithelial–mesenchymal transition in drug-resistant lung cancer

Acquired drug resistance and epithelial–mesenchymal transition (EMT) mediated metastasis are two highly interacting determinants for non-small-cell lung cancer (NSCLC) prognosis. This study investigated the common mechanisms of drug resistance and EMT from the perspective of metabolic reprogramming, which may offer new ideas to improve anticancer therapy. Acquired resistant cells were found to grow faster and have a greater migratory and invasive capacity than their parent cells. Metabolomics analysis revealed that acquired resistant cells highly relied on glutamine utilization and mainly fluxed into oxidative phosphorylation energy production. Further mechanistic studies screened out glutamate dehydrogenase 1 (GLUD1) as the determinant of glutamine addiction in acquired resistant NSCLC cells, and provided evidence that GLUD1-mediated α-KG production and the accompanying reactive oxygen species (ROS) accumulation primarily triggered migration and invasion by inducing Snail. Pharmacological and genetic interference with GLUD1 in vitro significantly reversed drug resistance and decreased cell migration and invasion capability. Lastly, the successful application of R162, a selective GLUD1 inhibitor, to overcome both acquired resistance and EMT-induced metastasis in vivo, identified GLUD1 as a promising and druggable therapeutic target for malignant progression of NSCLC. Collectively, our study offers a potential strategy for NSCLC therapy, especially for drug-resistant patients with highly expressed GLUD1.

Proteomic and Phosphoproteomic Analyses Reveal the Oncogenic Role of PTK7-NDRG1 Axis in Non-small-cell Lung Cancer Cell Resistance to AZD9291.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the most important chemotherapeutics for non-small-cell lung cancer (NSCLC) therapy. The resistance to EGFR-TKIs is one of the biggest obstacles to NSCLC outcome. In this study, taking advantage of phospho- and proximal proteomic techniques, we analyzed the network rearrangement in cell lines responding to AZD9291 treatment and found that cell-cell adhesion was dramatically enhanced in AZD9291-resistant cells. Further analysis revealed that protein tyrosine kinase 7 (PTK7) expression was significantly elevated. Knockdown or overexpression assays showed that PTK7 played a critical role in improving cell adhesion, which enhanced drug resistance. Because PTK7 is a membrane-localized pseudokinase, the proximal labeling probe BirA* was fused to reveal PTK7-interacting proteins. We found that PTK7 interacted with and stabilized NDRG1, which is located predominantly adjacent to adherens junctions. Downregulation of PTK7 or NDRG1 eliminated the resistance of H1975-resistant (H1975-R) and PC9-resistant (PC9-R) cells to AZD9291, suggesting that the PTK7-NDRG1 axis might be a potential target to eliminate the EGFR-TKI resistance during NSCLC therapy.

Deciphering the Impact of HER2 Alterations on Non-Small-Cell Lung Cancer: From Biological Mechanisms to Therapeutic Approaches.

Despite the recent increase in the number of types of treatments, non-small-cell lung cancer (NSCLC) remains the major cause of death from cancer worldwide. So, there is an urgent need to develop new therapeutic strategies. The HER2 gene codes for tyrosine kinase receptor whose alterations are known to drive carcinogenesis. HER2 alterations, including amplification, mutations, and overexpression, have been mainly described in breast and gastric cancers, but up to 4% of NSCLC harbor actionable HER2 mutations. HER2-targeted therapy for NSCLC with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate an improvement in survival. Nevertheless, recent data from phase II trials have shed light on promising specific therapies for HER2-mutant NSCLC such as trastuzumab deruxtecan. Herein, we aimed to provide an updated review on the biology, epidemiology, molecular testing, and therapeutic strategies for NSCLC with HER2 molecular alterations.

Post-protocol therapies in first-line immunotherapy trials in non–small cell lung cancer (NSCLC).

125 Background: The advent of immunotherapy (IO) has led to significant improvement in outcomes for patients (pts) with advanced non-small cell lung cancer (adv NSCLC). The rate of crossovers and receipt of post-protocol IO in pivotal trials leading to FDA approvals of IO in NSCLC has not been systematically evaluated. Here, we evaluate crossover rates and post protocol therapies for pts with adv NSCLC across multiple first-line (1L) IO monotherapy and chemotherapy/IO (chemo/IO) combination trials. Methods: We utilized the publicly available data from pivotal clinical trials leading to approvals of IO or chemo/IO regimens in 1L treatment of adv NSCLC. We extracted data on outcomes, rate of crossover from control arm to IO, proportion of pts in control arm receiving IO and the start dates of these clinical trials. The primary outcomes were the rates of crossover and the proportion of patients in control arms who received post-control IO. Results: The study included 4 trials with IO monotherapy and 12 trials with chemo/IO combinations in 1L adv NSCLC. The primary endpoints for these trials were PFS (25%), OS (19%), and both PFS and OS (56%). The crossover rate from control arm to experimental arm (with IO) ranged from 0-74% in IO monotherapy trials and 0-49% in chemo/IO trials. Two IO monotherapy trials and five chemo/IO trials did not allow crossover; among them, 3 trials had a PFS/OS co-primary endpoint, while others had OS as primary endpoint. Ten of 16 trials provided explicit information on use of subsequent post-protocol therapies in their publications. Among the two IO monotherapy trials which did not allow crossover, post-protocol IO was administered in only 20-30% of patients. Among the six chemo/IO trials with information on post-protocol therapies, 30%-59% patients on the control arm subsequently received some form of IO on progression. Nine of 12 trials started accrual after 10/2015, when nivolumab was approved in the United States as second-line (2L) therapy for adv NSCLC regardless of tumor PD-L1 expression. Conclusions: Despite the highly significant OS benefit from 2L IO, which was the standard of care (SOC) in the United States, the rates of crossover and post-protocol IO administration was distressingly low in 1L IO monotherapy and chemo/IO trials for 1L adv NSCLC. This low rate of 2L treatment with IO may have been due to limited global availability prior to widespread regulatory approval during the conduct of these trials. There is an increased need for consistency in reporting of crossover treatment and post-protocol treatments to allow adequate assessment of the true 1L benefit with IO. Control arms in pivotal trials require scrutiny to ensure confirmation with SOC to provide access to optimal treatments for patients and prevent magnification of observed benefits in experimental arms. The difficulty lies in the global conduct of large randomized clinical trials with differing regulatory approvals.

Mesoporous Silica Particles Functionalized with Newly Extracted Fish Oil (Omeg@Silica) Reducing IL-8 Counteract Cell Migration in NSCLC Cell Lines

Lung cancer is one of the leading forms of cancer in developed countries. Interleukin-8 (IL-8), a pro-inflammatory cytokine, exerts relevant effects in cancer growth and progression, including angiogenesis and metastasis in lung cancer. Mesoporous silica particles, functionalized with newly extracted fish oil (Omeg@Silica), are more effective than the fish oil alone in anti-proliferative and pro-apoptotic effects in non-small cell lung cancer (NSCLC) cell lines. The mechanisms that explain this efficacy are not yet understood. The aim of the present study is therefore to decipher the anti-cancer effects of a formulation of Omeg@Silica in aqueous ethanol (FOS) in adenocarcinoma (A549) and muco-epidermoid (NCI-H292) lung cancer cells, evaluating cell migration, as well as IL-8, NF-κB, and miRNA-21 expression. Results show that in both cell lines, FOS was more efficient than oil alone, in decreasing cell migration and IL-8 gene expression. FOS reduced IL-8 protein release in both cell lines, but this effect was only stronger than the oil alone in A549. In A549, FOS was able to reduce miRNA-21 and transcription factor NF-κB nuclear expression. Taken together, these data support the potential use of the Omeg@Silica as an add-on therapy for NSCLC. Dedicated studies which prove clinical efficacy are needed.

A Delphi consensus panel about clinical management of early-stage EGFR-mutated non-small cell lung cancer (NSCLC) in Spain: a Delphi consensus panel study

PurposeThis Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC).MethodsA modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements).ResultsIn round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB–IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib.ConclusionsThis Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario.

A multifunctional non-viral vector for the delivery of MTH1-targeted CRISPR/Cas9 system for non-small cell lung cancer therapy

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system adapted from bacteria is a programmable nuclease-based genome editing tool. The long-lasting effect of gene silencing or correction is beneficial in cancer treatment. Considering the need to broaden the practical application of this technology, highly efficient non-viral vectors are urgently required. We prepared a multifunctional non-viral vector that could actively target tumor cells and deliver CRISPR/Cas9 plasmids into nuclei of cancer cells. Protamine sulfate (PS) which contains nuclear localization sequence was utilized to condense plasmid DNA and facilitate nuclei-targeted delivery. Liposome-coated protein/DNA complex avoided the degradation of nuclease in blood circulation. The obtained PS@Lip/pCas9 was further modified with distearoyl phosphoethanolamine-polyethylene glycol-hyaluronic acid (HA) to endow the vector ability to actively target tumor cell. Results suggested that PS@HA-Lip could deliver CRISPR/Cas9 plasmids into nuclei of tumor cells and induce genome editing effect. With the disruption of MTH1 (mutT homolog1) gene, the growth of non-small cell lung cancer was inhibited. Moreover, cell apoptosis in tumor tissue was promoted, and liver metastasis of non-small cell lung cancer (NSCLC) was reduced. Our study has provided a therapeutic strategy targeting MTH1 gene for NSCLC therapy. Statement of significanceCRISPR/Cas9 as a powerful tool for genome editing has drawn much attention. The long-lasting effect possesses unique advantage in cancer treatment. Non-viral vectors have high loading capacity, high safety and low immunogenicity, playing an important role in CRISPR/Cas9 delivery. In our study, a multifunctional non-viral vector for the efficient delivery of CRISPR/Cas9 plasmid was constructed. With the active targeting ligand and nuclei-targeting component, the cargo was efficiently delivered into cell nuclei and exerted genome editing effect. By using this vector, we successfully inhibited the growth and induced the apoptosis of non-small cell lung cancer by disrupting MTH1 expression with good safety. Our work provided an efficient non-vial vector for CRISPR/Cas9 delivery and explored the possibility for cancer treatment.

Increased Utilization of Stereotactic Body Radiotherapy is Associated with Decreased Disparities and Improved Survival for Early-Stage NSCLC

IntroductionWe sought to determine if increased use of stereotactic body radiation therapy (SBRT) was associated with decreased disparities in the receipt of definitive treatment for early-stage non-small cell lung cancer (NSCLC). MethodsThe National Cancer Database (NCDB) was utilized to determine the proportion of patients with NSCLC receiving surgery, SBRT, or no definitive treatment for clinical cT1-2aN0M0 NSCLC from 2004-2017. Univariable and multivariable logistic regressions were used. Age-adjusted mortality rates were calculated using the Surveillance, Epidemiology, and End Result (SEER) database. ResultsFrom 2004 to 2017, the proportion of early-stage NSCLC undergoing no definitive treatment declined from 22% to 10.5% (P<.001), while the proportion receiving SBRT increased from 1% (0.9%-1.3%) to 22% (21.4%-22.3%; P<.001). Among Whites, the proportion undergoing no definitive treatment decreased from 21% to 10% (P<.001), as compared to Blacks, which had a higher decrease, of 32% to 15% (P<.001). The proportion of Blacks receiving SBRT increased from 1% (0.3%-1.7%) to 22% (20.8%-23.5%) (P<.001). Between 2011 and 2017 likelihood of Blacksreceiving curative therapy increased compared to Whites [OR: 0.55 (0.48-0.64) to 0.70 (0.62-0.79; P<.001]. Furthermore, the age-adjusted mortality rate of early-stage NSCLC decreased from 4.3 (4.0-4.5) in 2004 to 0.8 (0.7-0.9) in 2017 (P<.001). ConclusionsIncreased utilization of SBRT significantly increased the proportion of patients receiving curative therapy for early-stage NSCLC and was associated with an improvement in mortality. Furthermore, the use of SBRT reduced previously seen disparities in receipt of treatment between Whites and Blacks. SBRT was also associated with decreased mortality from early-stage NSCLC.

A novel ligand-modified nanocomposite microparticles improved efficiency of quercetin and paclitaxel delivery in the non-small cell lung cancer

Chemotherapy is the first choice for the treatment of cancer but it is still limited by insufficient kill efficiency and drug resistance. These problems urgently need to be overcome in a way that minimizes damage to the body. In this study, we designed the nanocomposite microparticles (NMPs) modified by cetuximab (Cet) and loaded anti-tumor agents- quercetin (QUE) and paclitaxel (PTX)- for eliciting specific drugs homing and enhancing the killing efficiency of chemotherapy drugs (P/Q@CNMPs). Physicochemical characteristics results presented that P/Q@CNMPs have a suitable aerodynamic diameter and uniform morphology that could meet the requirements of particles deposition in the lung. And it also had the characteristics of sustained-release and pH-responsive which could release the agents in the right place and has a continuous effect. In vitro and in vivo analysis results presented that P/Q@CNMPs have the accuracy targeting ability and killing effect on non-small cell lung cancer (NSCLC) which express positive epidermal growth factor receptor (EGFR) on the membrane. Furthermore, this system also has low toxicity and good biocompatibility. These results demonstrated that P/Q@CNMPs could be a potential intelligent targeting strategy used for chemo-resistant NSCLC therapies.

Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non–small cell lung cancer

Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold (i.e., tumors with limited tumor-infiltrating lymphocytes) tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR-WT NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC, with significant enrichment of the cholesterol gene signature, indicating that targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and can also drastically reverse the phenotype of immuno-cold to an inflamed phenotype in vivo. This change led to a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a clinical insight to treat NSCLC patients with immuno-cold tumors.

Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models.

Non-small-cell lung cancer (NSCLC) is known as one of the most lethal cancers, causing more than 1 million deaths annually worldwide. Therefore, the development of novel therapeutic drugs for NSCLC has become an urgent need. Herein, various mouse models provide great convenience not only for researchers but also for the development of antitumor drug. Meanwhile, TCM, as a valuable and largely untapped resource pool for modern medicine, provides research resources for the treatment of various diseases. Until now, cell-derived xenograft (CDX) model, patient-derived xenograft (PDX) model, syngeneic model, orthotopic model, humanized mouse model (HIS), and genetically engineered mouse models (GEMMs) have been reported in TCM evaluation. This review shows the role and current status of kinds of mouse models in antitumor research and summarizes the application progress of TCM including extracts, formulas, and isolated single molecules for NSCLC therapy in various mouse models; more importantly, it provides a theoretical exploration of what kind of mouse models is ideal for TCM efficacy evaluation in future. However, there are still huge challenges and limitations in the development of mouse models specifically for the TCM research, and none of the available models are perfectly matching the characteristics of TCM, which suppress the tumor growth through various mechanisms, especially by regulating immune function. Nevertheless, with fully functional immune system existing in syngeneic model and humanized mouse model (HIS), it is still suggested that these two models are more suitable for development of TCM especially for TCM extracts or formulas. Moreover, continued efforts are needed to generate more reliable mouse models to test TCM formulas in future research.

Biomimetic Red Blood Cell Membrane-Mediated Nanodrugs Loading Ursolic Acid for Targeting NSCLC Therapy.

Simple SummaryLung cancer is the second most common cancer after breast cancer. Non-small-cell lung cancer, which represents more than 85% of all lung cancer subtypes, is known for its tumor progression and metastasis, resulting in poor clinical outcomes. Conventional therapies for NSCLC, such as surgery, chemotherapy, and radiotherapy, always fail due to therapeutic resistance. In recent years, ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been shown to be a promising antitumor drug by regulating multiple signaling pathways in cancers. Unfortunately, the poor water solubility, low bioavailability, and systemic toxicity of UA limit its clinical application. In this study, a biomimetic red blood cell membrane nanocarrier was developed to deliver UA to targeted tumor sites efficiently, and it inhibited tumor growth by inducing the apoptosis and autophagy of cancer cells both in vitro and in vivo.As one of the most common cancers worldwide, non-small-cell lung cancer (NSCLC) treatment always fails owing to the tumor microenvironment and resistance. UA, a traditional Chinese medicine, was reported to have antitumor potential in tumor models in vitro and in vivo, but showed impressive results in its potential application for poor water solubility. In this study, a novel biomimetic drug-delivery system based on UA-loaded nanoparticles (UaNPs) with a red blood cell membrane (RBCM) coating was developed. The RBCM-coated UANPs (UMNPs) exhibited improved water solubility, high stability, good biosafety, and efficient tumor accumulation. Importantly, the excellent antitumor efficiency of the UMNPs was confirmed both in vitro and in vivo in cancer models. In addition, we further investigated the antitumor mechanism of UMNPs. The results of Western blotting showed that UMNPs exerted an anticancer effect by inducing the apoptosis and autophagy of NSCLC cells, which makes it superior to free UA. In addition, body weight monitoring, hematoxylin and eosin (HE) analysis, and immunohistochemical (IHC) analysis showed no significant difference between UMNPs and the control group, indicating the safety of UMNPs. Altogether, the preparation of biomimetic UMNPs provides a promising strategy to improve outcomes in NSCLC.

The Glasgow Prognostic Score Predicts Outcomes of Pembrolizumab or Atezolizumab Monotherapy in Patients with Pretreated Non-Small Cell Lung Cancer

Introduction: Predictors of the effectiveness of immune checkpoint inhibitor (ICI) monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) remain ill-defined. We investigated whether the Glasgow prognostic score (GPS) could serve as such predictors. Methods: Eighty patients treated with pembrolizumab or atezolizumab monotherapy as second- or subsequent-line therapy for NSCLC were retrospectively reviewed, and the associations between GPS, body mass index (BMI), and each of progression-free survival (PFS) and overall survival (OS) were assessed. Results: The median follow-up period was 11.1 months. Patients with a BMI ≥20.4 kg/m2 had significantly longer PFS and OS (3.7 and 22.2 month, respectively) than did those with a BMI <20.4 kg/m2 (2.2 and 11.5 months, respectively). Patients with a GPS of 0 had a significantly longer PFS (6.6 months) than did those with a GPS of 1 (2.2 months, p = 0.002) and 2 (1.8 months, p = 0.029). Patients with a GPS of 0 also had a significantly longer OS (22.2 month) than did those with a GPS of 1 (9.2 months, p = 0.002) and 2 (4.7 months, p = 0.002). Notably, the GPS, BMI, and clinical stage were independent predictors of PFS, while the GPS and performance status were independent predictors of OS. The response rate of patients with a GPS of 0 was significantly higher than that of patients with a GPS of 1–2 (26.2% vs. 7.9%, p = 0.03). Conclusion: The GPS is an independent predictor of PFS and OS in patients with NSCLC who received second- or subsequent-line pembrolizumab or atezolizumab monotherapy.

Non-small cell lung cancer in China.

In China, lung cancer is a primary cancer type with high incidence and mortality. Risk factors for lung cancer include tobacco use, family history, radiation exposure, and the presence of chronic lung diseases. Most early‐stage non‐small cell lung cancer (NSCLC) patients miss the optimal timing for treatment due to the lack of clinical presentations. Population‐based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China. The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC, thus prolonging survival in patients with positive drivers. In the exploration of immune escape mechanisms, programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitor monotherapy and PD‐1/PD‐L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China. In the Chinese Society of Clinical Oncology's guidelines for NSCLC, maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy. Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC. In this review, we summarized recent advances in NSCLC in China in terms of epidemiology, biology, molecular pathology, pathogenesis, screening, diagnosis, targeted therapy, and immunotherapy.

The O-glycosylating enzyme GALNT2 acts as an oncogenic driver in non-small cell lung cancer

BackgroundN-Acetylgalactosaminyltransferases (GALNTs), the enzymes that initiate mucin-type O-glycosylation, are closely associated with tumor occurrence and progression. However, a comprehensive analysis of GALNTs in non-small cell lung cancer (NSCLC) is lacking.MethodsThe expression profiles and prognostic values of the GALNT family members in NSCLC were analyzed using publicly available databases. Gain- and loss-of-function experiments were applied to assess the biological function of GALNT2 in NSCLC. High-throughput sequencing and bioinformatics approaches were employed to uncover the regulatory mechanism of GALNT2.ResultsAmong the family members of GALNTs, only GALNT2 was frequently overexpressed in NSCLC tissues and was positively correlated with poor prognosis. In vitro assays showed that GALNT2 knockdown repressed NSCLC cell proliferation, migration, and invasion, but induced apoptosis and cell cycle arrest. Correspondently, GALNT2 overexpression exerted the opposite effects. In vivo experiments demonstrated that knockdown of GALNT2 restrained tumor formation in nude mice. Mechanistic investigations revealed that GALNT2 modified the O-glycosylation of ITGA5 and affected the activation of the PI3K/Akt and MAPK/ERK pathways. Further studies showed that miR-30d was a negative regulator of GALNT2.ConclusionsThese findings suggest that GALNT2 is an oncogene in NSCLC and has the potential as a target for NSCLC therapy.

Implications of m6A methylation and microbiota interaction in non-small cell lung cancer: From basics to therapeutics.

N6-methyladenine (m6A) is one of the most common RNA epigenetic modifications in all higher eukaryotes. Increasing evidence demonstrated that m6A-related proteins, acted as oncogenes or tumor suppressors, are abnormally expressed in the cell lines and tissues of non-small cell lung cancer (NSCLC). In addition, lung as the special immune organ contacts with the outer environments and thereby inevitably suffers from different types of microbial pathogen attack. Those microbial pathogens affect the development, progression, and clinical outcomes of NSCLC via altering host m6A modification to disrupt pulmonary immune homeostasis and increase the susceptibility; conversely, host cells modulate m6A modification to repress bacterial colonization. Therefore, m6A harbors the potential to be the novel biomarkers and targets for predicting poor prognosis and chemotherapy sensitivity of patients with lung cancer. In this paper, we provided an overview of the biological properties of m6A-modifying enzymes, and the mechanistic links among lung microbiota, m6A modification and NSCLC. Although the flood of novel m6A-related inhibitors represents many dramatic improvements in NSCLC therapy, their efficacy and toxicity in NSCLC are explored to address these pivotal gaps in the field.

The expression and biological effect of NR2F6 in non-small cell lung cancer.

ObjectiveThis study aimed to explore the expression and effect of the nuclear receptor subfamily 2 group F member 6 (NR2F6) gene in non-small cell lung cancer (NSCLC) and provide an experimental basis for the targeted therapy of NSCLC.MethodFirst, the expression of NR2F6 in lung cancer tissues was analyzed using the Gene Expression Omnibus and the Cancer Genome Atlas (TCGA) databases, and the expression of NR2F6 in lung cancer tissues and cells was verified by Western blotting and quantitative polymerase chain reaction. Next, the relationship between NR2F6 expression and the clinicopathological features of lung cancer was analyzed via immunohistochemistry, and the relationship between NR2F6 expression and prognosis was analyzed using the Kaplan–Meier Plotter. The influence of NR2F6 knockdown on the proliferation capacity of lung cancer cells was then verified at cell level. Finally, the expression of heterogeneous nuclear ribonucleoprotein D (HNRNPD) in lung cancer tissue was analyzed using the TCGA database and immunohistochemistry. The impact of HNRNPD knockdown on the proliferation capacity of lung cancer cells was verified at cell level, and the relationship between NR2F6 and HNRNPD was verified by co-immunoprecipitation.ResultsNR2F6 was highly expressed in lung cancer tissues and cells, and its expression was positively correlated with the depth of invasion, lymphatic metastasis, and clinical stage of lung cancer. High expression of NR2F6 in lung cancer was also significantly associated with poor prognosis. At cell level, NR2F6 knockdown was found to inhibit the proliferation of H460 and H358 in lung cancer cells. Furthermore, the TCGA database and immunohistochemical results showed that HNRNPD was highly expressed in lung cancer tissues and was highly consistent with NR2F6 expression in these tissues. Knockdown of HNRNPD also inhibited the proliferation of lung cancer cells. The co-immunoprecipitation experiment verified that NR2F6 interacted with HNRNPD.ConclusionNR2F6 may interact with HNRNPD to jointly regulate the progression of lung cancer, and this conclusion provides a new experimental basis for the study of the molecular targeted therapy of NSCLC.

EP08.02-158 Final Analyses of ALTER-L018: A Randomized Phase II Trial of Anlotinib Plus Docetaxel vs Docetaxel as 2nd-line Therapy for EGFR-negative NSCLC

Docetaxel is one of the standard 2nd-line treatments for advanced non-small cell lung cancer (NSCLC), but the effect is limited. The combination of docetaxel and ramucirumab/nintedanib has demonstrated antitumor activity as 2nd-line therapy in advanced NSCLC. Anlotinib, an oral multi-target angiogenesis, can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial (ALTER0303). We conducted ALTER-L018 to evaluate improvement of the efficacy and safety of anlotinib plus docetaxel in EGFR-negative advanced NSCLC.