In recent years, series of driver genes, such as EGFR, KRAS/NRAS, BRAF, PIK3CA, ALK and ROS1 and so on, have been found in non-small cell lung cancer (NSCLC) one after another with the development of molecular detecting technology. Targeted drugs bring benefits for these NSCLC patients with driver gene variations. However, some NSCLC did not have any known driver gene variations; we called it pan-negative lung cancer. In this paper, we summarize the concept, clinical pathological characteristics, the epidemiological characteristics, treatment and prognosis of pan-negative NSCLC.
Carcinoma, Non-Small-Cell Lung ; diagnosis ; drug therapy ; genetics ; pathology ; Humans ; Lung Neoplasms ; diagnosis ; drug therapy ; genetics ; pathology ; Mutation ; Prognosis

Recently, targeted therapy has achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. Mesenchymal to epithelial transition factor (MET) is considered to be another important molecular target for NSCLC since epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Accumulating clinical trials and case reports have confirmed that MET inhibitors exhibited a potential prospect in treating patients with MET 14 exon skipping alterations, suggesting that MET 14 exon skipping mutation might be an effective biomarker for MET inhibitors, which remains to be confirmed by more clinical data. This review summarizes current research about the molecular mechanism, clinicopathological characterization, treatment strategies and drug resistance mechanisms of MET 14 exon skipping alterations in NSCLC.
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Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Exons ; genetics ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; Molecular Targeted Therapy ; Mutation ; Proto-Oncogene Proteins c-met ; genetics

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrous interstitial lung disease of unknown etiology. IPF is also considered to be among the independent risk factors for lung cancer, increasing the risk of lung cancer by 7% and 20%. The incidence of IPF complicated with lung cancer, especially non-small cell lung cancer (NSCLC), is increasing gradually, but there is no consensus on unified management and treatment. IPF and NSCLC have similar pathological features. Both appear in the surrounding area of the lung. In pathients with IPF complicated with NSCLC, NSCLC often develops from the honeycomb region of IPF, but the mechanism of NSCLC induced by IPF remains unclear. In addition, IPF and NSCLC have similar genetic, molecular and cellular processes and common signal transduction pathways. The universal signal pathways targeting IPF and NSCLC will become potential therapeutic drugs for IPF complicated with NSCLC. This article examines the main molecular mechanisms involved in IPF and NSCLC and the research progress of drugs under development targeting these signal pathways.
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Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Idiopathic Pulmonary Fibrosis/drug therapy* ; Lung Neoplasms/genetics* ; Lung/pathology* ; Signal Transduction

The clinical application of immune checkpoint inhibitors (ICIs) lead to dramatic changes in the treatment strategy for patients with advanced non-small cell lung cancer (NSCLC), but the efficacy of ICIs in oncogene-driven NSCLC is controversial. Existing research shows that the efficacy of ICIs may be related to different types of driver genes, programmed cell death-ligand 1 (PD-L1) level, and tumor mutational burden (TMB). It may involved in other factors, such as clinical characteristics, and immune cell density. ICIs monotherapy or combination therapy may play a role in a subset of oncogene-driven NSCLC patients, but further studies are needed to select these patients, which may be an important direction for the future development of advanced NSCLC.
B7-H1 Antigen ; genetics ; Biomarkers, Tumor ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; Humans ; Immunotherapy ; Lung Neoplasms ; drug therapy

DNA damage repair (DDR) system plays an important role in maintaining of genomic stability. Accumulation of DNA lesions or deficiency of DDR system could drive tumorigenesis as well as promote tumor progression; meanwhile, they could also provide therapeutic opportunities and targets. Of all the antineoplastic agents of lung cancers, many of them targeted or were associated with DNA damage and repair pathways, such as chemotherapies and antibody-drug conjugates which were designed directly causing DNA damages, targeted drugs inhibiting DNA repair pathways, and immune-checkpoint inhibitors. In this review, we described the role of DNA damage and repair pathways in antitumor activity of the above agents, as well as summarized the application and clinical investigations of these antineoplastic agents in lung cancers, in order to provide more information for exploring precision and effective strategies for the treatment of lung cancer based on the mechanism of DNA damage and repair.
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Antineoplastic Agents/therapeutic use* ; DNA Damage ; DNA Repair ; Humans ; Lung Neoplasms/genetics* ; Neoplasms/drug therapy*

BACKGROUND: Epidermal growth factor receptor (EGFR) and cellular-mesenchymal to epithelial transition factor (c-Met) are widely expressed on cancer cells. There is a synergistic effect of EGFR and HGF/c-Met pathways on proliferation, downstream activation of signal transduction and an additive effect. Studies show that combination of both signaling pathways could potentially be targeted in a synergistic fashion. Amivantamab, a bispecific monoclonal antibody targeting EGFR and c-Met, yielded robust and durable responses in a variety of clinicals trials. However, few researches have reported its efficacy in Chinese non-small cell lung cancer (NSCLC) patients. This study was conducted to evaluate the effectiveness and tolerance of Amivantamab in NSCLC patients with EGFR/MET gene abnormalities at Peking University Cancer Hospital. METHODS: The study enrolled NSCLC patients who received Amivantamab in our hospital between August 2020 and December 2021, and analyzed the response, survival, and treatment-related adverse events. RESULTS: Fifteen patients were enrolled in this research, and six of them received Amivantamab treatment and the other nine patients received Amivantamab plus Lazertinib treatment. The rates of partial response (PR), stable disease (SD), and progressive disease (PD) were 46.7% (7/15), 46.7% (7/15) and 6.7% (1/15), respectively. The overall response rate (ORR) and disease control rate (DCR) were 28.6% (2/7) and 100.0% (7/7) in seven patients with EGFR exon 20 insertion, respectively. The ORR and DCR were 40.0% (2/5) and 100.0% (5/5) in five post-osimertinib EGFR-mutant patients, respectively. After a median follow-up of 8.7 months, the median progression-free survival and overall survival were not reached. The most common treatment-related adverse events were rash (86.7%), paronychia (80.0%), and infusion-related reactions (60.0%), and most of them were graded as 1 to 2. Grade 3 to 4 adverse events included rash (33.3%), alanine aminotransferase elevation (13.3%), gamma-glutamyl transpeptidase elevation (13.3%), peripheral edema (6.7%), thromboembolism (6.7%), interstitial lung disease (6.7%), and thrombocytopenia (6.7%). CONCLUSIONS Amivantamab was effective in Chinese NSCLC patients with EGFR exon 20 insertion and post-Osimertinib EGFR-mutant patients, similar to the results of clinical trials conducted in western countries. Amivantamab was well tolerated and emphases should be put on adverse events such as rash, paronychia, and infusion-related reactions.
Antibodies, Bispecific ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Exanthema/drug therapy* ; Humans ; Lung Neoplasms/genetics* ; Mutation ; Paronychia/drug therapy* ; Protein Kinase Inhibitors/therapeutic use*

With the development of medical technology, tumor vaccines as a novel precise immunotherapy approach have gradually received attention in clinical applications. Against the backdrop of the global corona virus disease 2019 (COVID-19) outbreak, vaccine technology has further advanced. Depending on the types of antigens, tumor vaccines can be divided into whole-cell vaccines, peptide vaccines, messenger ribonucleic acid (mRNA) vaccines, recombinant virus vaccines, etc. Although some tumor vaccines have been marketed and achieved certain therapeutic effects, the results of tumor vaccines in clinical trials have been unsatisfactory in the past period. With the maturation of next-generation sequencing (NGS) technology and the continuous development of bioinformatics, dynamic monitoring of the entire process of tumor subpopulation development has become a reality, which has laid a solid foundation for personalized, neoantigen-centered therapeutic tumor vaccines. This article reviews the recent developments of tumor vaccines of different types, starts with lung cancer and summarizes the achievements of tumor vaccines in clinical applications, and provides an outlook for the future development of antigen-centered tumor vaccines.
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Humans ; Cancer Vaccines/therapeutic use* ; Antigens, Neoplasm ; Lung Neoplasms/drug therapy* ; Neoplasms/genetics* ; Computational Biology ; Immunotherapy/methods* ; Lung

Squamous cell lung cancer (SqCLC) is a unique clinical and histologic category of non-small cell lung cancer (NSCLC). Most of patients with SqCLC tend to be older, typically at advanced stage, associated with smoking and have more complications. With progress of targeted therapy of lung cancer, we identified several potential actionable genetic abnormalities such as FGFR. Several FGFR inhibitors have been approved for clinical use in different cancers. And some of these agents are currently under investigation in clinical trials for SqCLC. This article summarizes the current knowledge about FGFR aberrations, the relative inhibitors in development and clinical data in SqCLC.
Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; metabolism ; Carcinoma, Squamous Cell ; drug therapy ; genetics ; metabolism ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; Molecular Targeted Therapy ; methods ; Mutation ; Receptors, Fibroblast Growth Factor ; genetics ; metabolism

OBJECTIVES: Given the roles of bcl-2, bax and p53 in apoptosis, we investigated the effect of their expression on the response to cisplatin in order to understand the molecular events of cisplatin-resistance in lung cancers. METHODS: Three parental human lung cancer cell lines (PC9, PC14 and H69) and their in vitro selected cisplatin-resistant sublines were examined. Cells treated with cisplatin were processed for acridine orange and ethidium bromide staining and DNA gel electrophoresis for the morphologic detection of apoptosis. The endogenous levels of bcl-2, bax and p53 protein expression in lung cancer cells were assessed by Western blot analysis and DNA of polymerase chain reaction-amplified exon 5 to 8 of p53 gene was directly sequenced. RESULTS: H69, which had bcl-2 expression, p53 mutation and decreased expression of p53 and bax, was relatively resistant to cisplatin and delayed and reduced apoptosis. Although apoptosis was markedly reduced in cisplatin-resistant sublines compared to their parental cells, there were no significant differences in the expression of p53, bcl-2 and bax. CONCLUSIONS: Cisplatin-resistance was associated with the reduced cellular susceptibility to apoptosis. Cancer cells with the natural expression of bcl-2 and p53 mutation may be more resistant to cisplatin and less susceptible to apoptosis.
Antineoplastic Agents/pharmacology* ; Apoptosis/genetics ; Apoptosis/drug effects* ; Cisplatin/pharmacology* ; Drug Resistance ; Gene Expression ; Genes, bcl-2 ; Genes, p53 ; Human ; Lung Neoplasms/pathology ; Lung Neoplasms/genetics ; Lung Neoplasms/drug therapy ; Proto-Oncogene Proteins/genetics ; Tumor Cells, Cultured

BACKGROUND: The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear. METHODS: A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization. RESULTS: There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not. CONCLUSIONS In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.
Camptothecin/therapeutic use* ; Glucuronosyltransferase/genetics* ; Humans ; Lung Neoplasms/drug therapy* ; Mutation ; Polymorphism, Genetic ; Retrospective Studies