Treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can achieve good disease control, but it will inevitably produce drug resistance. About 3%-10% of the resistance mechanism is small cell transformation. Two cases of stage IV lung adenocarcinoma with EGFR mutation were reported and the disease was controlled after EGFR-TKIs treatment. In case 1, progression-free survival (PFS) before small cell carcinoma transformation was 16 months, and in case 2, PFS before small cell carcinoma transformation was 24 months. Subsequent biopsy after disease progression indicated a shift to small cell lung cancer. Case 1 PFS after small cell carcinoma transformation was 6 months, and case 2 PFS after small cell carcinoma transformation was 8 months, and overall survival (OS) was 36 months, which significantly prolonged the patient's survival. At the same time, the literature of such drug resistance mutations was reviewed. For patients with advanced NSCLC with sensitive mutations, it is necessary to conduct secondary histopathological tests after TKIs treatment resistance, and select subsequent treatment according to different resistance mechanisms for the whole course of disease management.
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Humans ; Carcinoma, Small Cell ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Adenocarcinoma/genetics* ; Small Cell Lung Carcinoma/genetics* ; ErbB Receptors/genetics*

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations ("target-dependent resistance") and in the parallel and downstream pathways ("target-independent resistance"). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Tumor Microenvironment/genetics*

BACKGROUND: The switch/sucrose nonfermentable chromatin-remodeling (SWI/SNF) complex is a pivotal chromatin remodeling complex, and the genomic alterations (GAs) of the SWI/SNF complex are observed in several cancer types, correlating with multiple biological features of tumor cells. However, their role in liver metastasis of non-small cell lung cancer (NSCLC) remains unclear. Our study aims to investigate the role and potential mechanisms underlying NSCLC liver metastasis induced by the GAs of SWI/SNF complex. METHODS: The GAs of SWI/SNF complex in NSCLC cell lines (H1299, H23 and H460) were identified by whole-exome sequencing (WES). ARID1A knockout H1299 cell was constructed with the CRISPR/Cas9 technology. The mouse model of liver metastasis from NSCLC was established to simulate lung cancer liver metastasis and observe the metastasis rate under different gene mutation conditions. RNA sequencing and Western blot were conducted for differential gene expression analysis. Immunohistochemistry (IHC) analysis was used to assess protein expression levels of SWI/SNF-regulated target molecules in mouse liver metastases. RESULTS: WES analysis revealed intracellular gene mutations. The animal experiments demonstrated a correlation between the GAs of SWI/SNF complex and a higher liver metastasis rate in immunodeficient mice. Transcriptome sequencing and Western blot analysis showed upregulated expression of ALDH1A1 and APOBEC3B in SWI/SNF-mut cells, particularly in ARID1A-deficient H460 and H1299 sgARID1A cells. IHC staining of mouse liver metastases further demonstrated elevated expression of ALDH1A1 in the H460 and H1299 sgARID1A group. CONCLUSIONS This study underscores the critical role of the GAs of SWI/SNF complex, such as ARID1A and SMARCA4, in promoting liver metastasis of lung cancer cells. The GAs of SWI/SNF complex may promote liver-specific metastasis by upregulating ALDH1A1 and APOBEC3B expression, providing novel insights into the molecular mechanisms underlying lung cancer liver metastasis.
Animals ; Mice ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Liver Neoplasms/genetics*

Carcinoma, Non-Small-Cell Lung ; genetics ; Exons ; genetics ; Genes, erbB-1 ; genetics ; Humans ; Lung Neoplasms ; pathology

OBJECTIVES: To evaluate the sensitivity and specificity of immunohistochemistry (IHC) for detecting common epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and to estimate the cost-effectiveness of IHC testing. METHODS: A total of 208 NSCLC patients were included in the trial, and the EGFR mutation status in the patients were detected by PCR and IHC. Two mutation-specific antibodies against the most common exon 19 deletion (clone SP111) and exon 21 L858R mutation (clone SP125) were tested by using automated immunostainer. A cost-effectiveness analysis model was built for the analysis of optimal detection scheme. RESULTS: With a cutoff value of IHC 1+, the overall sensitivity and specificity of the IHC-based method compared with the PCR-based method were 81.7% (95% CI 72.4% to 89.0%) and 94.7% (95% CI 92.6% to 99.5%), respectively. EGFR 19del mutation was detected by SP111 antibody with a sensitivity of 65.9% (95% CI 49.4% to 79.9%) and specificity of 98.8% (95% CI 95.7% to 99.9%). EGFR L858R mutation was detected by SP125 antibody with a sensitivity of 94.2% (95% CI 84.1% to 98.8%) and specificity of 99.4% (95% CI 96.5% to 100%). The IHC and PCR cost ratio needed to be 1-to-3 or more in our patients to economically justify before the use of IHC. CONCLUSIONS The study confirms an excellent specificity with fairly good sensitivity of IHC and mutation-specific antibodies for common EGFR mutations. It is cost-effective to use IHC method to detect EGFR mutation first when the IHC and PCR cost ratio is 1-to-3 or more in Chinese populations.
Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Humans ; Immunohistochemistry ; Lung Neoplasms/genetics* ; Mutation

Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities.
Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; Drug Resistance, Neoplasm ; genetics ; Humans ; Lung Neoplasms ; genetics ; metabolism

Biopsy, Fine-Needle ; Carcinoma, Non-Small-Cell Lung/genetics* ; Consensus ; Humans ; Lung Neoplasms/genetics*

Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Pleural Effusion, Malignant ; Consensus ; China

Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Consensus ; China

Patients with oncogenic driver alterations of non-small cell lung cancer (NSCLC) can benefit from targeted therapy, but acquired resistance is inevitable ultimately. Epigenetic modifications, including DNA methylation, histone modifications, non-coding RNA-mediated regulate and chromatin remodeling, are important mechanisms of acquired resistance in targeted therapy of NSCLC. In recent years, studies have found that epigenetic modifications can effectively reverse drug resistance. Targeted therapy combined with epigenetic modifications may become a promising therapeutic strategy. Here, we review the progress of epigenetic mechanism in acquired resistance of targeted therapy in NSCLC, hoping to provide ideas for screening dominant population and overcoming resistance.
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Carcinoma, Non-Small-Cell Lung/genetics* ; DNA Methylation ; Epigenesis, Genetic ; Humans ; Lung Neoplasms/genetics*