A Decade-Old Atlas of TMEM (Transmembrane) Protein Family in Lung Cancer: Lessons Learnt and Future Directions.

Previous studies have shown that asthma is a risk factor for lung cancer, while the mechanisms involved remain unclear. We attempted to further explore the association between asthma and non-small cell lung cancer (NSCLC) via bioinformatics analysis. We obtained GSE143303 and GSE18842 from the GEO database. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) groups were downloaded from the TCGA database. Based on the results of differentially expressed genes (DEGs) between asthma and NSCLC, we determined common DEGs by constructing a Venn diagram. Enrichment analysis was used to explore the common pathways of asthma and NSCLC. A protein-protein interaction (PPI) network was constructed to screen hub genes. KM survival analysis was performed to screen prognostic genes in the LUAD and LUSC groups. A Cox model was constructed based on hub genes and validated internally and externally. Tumor Immune Estimation Resource (TIMER) was used to evaluate the association of prognostic gene models with the tumor microenvironment (TME) and immune cell infiltration. Nomogram model was constructed by combining prognostic genes and clinical features. 114 common DEGs were obtained based on asthma and NSCLC data, and enrichment analysis showed that significant enrichment pathways mainly focused on inflammatory pathways. Screening of 5 hub genes as a key prognostic gene model for asthma progression to LUAD, and internal and external validation led to consistent conclusions. In addition, the risk score of the 5 hub genes could be used as a tool to assess the TME and immune cell infiltration. The nomogram model constructed by combining the 5 hub genes with clinical features was accurate for LUAD. Five-hub genes enrich our understanding of the potential mechanisms by which asthma contributes to the increased risk of lung cancer.

Lung cancer is one of the most malignant tumor, representing a significant threat to human health. In China, its mortality rate is the highest among all malignant tumors. The occurrence of drug resistance has resulted in unfavourable prognosis for patients with lung cancer, and overcoming drug resistance is a significant challenge that needs to be addressed. Nano-drug delivery technology has been an important approach to overcome drug resistance in lung cancer. Targeting to the mechanisms of drug resistance, by enabling the combined delivery of drugs, increasing the efficiency of drug delivery and improving the targeting and safety of drugs, nano-drug delivery technology offers a novel approach to tackling drug resistance in lung cancer. This paper describes the current status of lung cancer treatment, mechanisms of drug resistance, strategies to overcome drug resistance, and the application of nanotechnology in the diagnosis and treatment of lung cancer. In addition, it summarizes the recent research progress on the application of nano-drug delivery technology to overcome drug resistance in lung cancer. Finally, the current prospects and challenges of nano-drug delivery technology are discussed. .

Enigmatic exosomal connection in lung cancer drug resistance

Lung cancer is the leading cause of all cancer-related mortality worldwide. The RAS-RAF-MEK-ERK (RAS-MAPK) signaling pathway is critical for maintaining cell survival and proliferation. Somatic mutations in the RAS or RAF genes are associated with frequent hyper-activation of RAS-MAPK pathway in non-small cell lung cancer or NSCLC. While direct inhibitors of KRAS G12C are emerging with promising efficacy, resistance to these agents as well as to inhibitors of RAF and MEK remains an obstacle to long-term patient survival. Therefore, it is essential to understand how drug resistance emerges in lung cancer and to identify bypass survival pathways or compensatory mechanisms that limit the response to RAS-MAPK targeted therapies in lung cancer. Emerging literature indicates a critical role of bromodomain and extra-terminal domain (BET) family of bromodomain proteins (BRD4, BRD3, BRD2) in various human malignancies and provides the rational for targeting BET proteins as a strategy for the development of new anticancer drugs. Using combinatorial drug screens in a panel of NSCLC cell lines, we found that BET proteins act in parallel to the RAS-MAPK pathway to promote drug resistance in lung cancer. Combination of BET and RAS-MAPK inhibitors caused pronounced cell death and potent tumor regression/stasis in several KRAS or BRAF mutant models of NSCLC with synergistic apoptosis induction and downregulation of MYC, a transcriptional target of BET proteins. However, concurrent loss of the tumor suppressor STK11 (aka LKB1) in NSCLC cells induced activation of the Hippo pathway effector and transcriptional co-activator, YAP and conferred resistance to the BET and RAS-MAPK inhibitors combination in NSCLC cells and tumors.These findings suggest an unprecedented functional interplay between BET chromatin regulators, Hippo-YAP and RAS-MAPK signaling in lung cancer and therapy resistance. Further, this study identified STK11 as a modifier of sensitivity to the BET and RAS-MAPK inhibitors combination in NSCLC cells and tumors. Citation Format: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Tracy Tang, Ben Powell, Trever Bivona. Targeting oncogenic transcription and signaling crosstalk fueling drug resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB451.

Lung cancer is the most common but fatal malignant tumor worldwide. Patients with lung cancer experienced a relatively low 5-year overall survival rate, and issues such as metastasis and drug resistance remain prominent challenges in its clinical management. Neddylation, a novel type of post-translational modification, was overactivated in lung cancer and was closely associated with its occurrence, development, metastasis, and drug resistance. This review systematically summarizes the biological process of neddylation and deeply explores the latest research progress on how neddylation affects lung cancer cell proliferation, metastasis, and drug resistance mechanisms, with a focus on its regulation of key molecules such as Cullin-RING E3 ligases and the SCCRO family. Meanwhile, it concludes the current advances in potential therapeutic agents targeting neddylation-related targets, including small-molecule compounds (such as Pevonedistat) and natural extracts (such as arctigenin). Finally, the review prospectively evaluates the application potential and questions requiring further exploration of neddylation in lung cancer treatment. In conclusion, we aim to systematically summarize the biological process of neddylation, critically explore its roles in lung cancer proliferation, metastasis, and drug resistance, and evaluate the therapeutic potential of neddylation-targeting agents.

MiR-451a attenuates doxorubicin resistance in lung cancer via suppressing epithelialmesenchymal transition (EMT) through targeting c-Myc

Circulating cell-free DNA (cfDNA) can be used to characterize tumor genomes through next-generation sequencing (NGS)-based approaches. We aim to identify novel genetic alterations associated with drug resistance in lung cancer and colorectal cancer patients who were treated with EGFR-targeted therapy and cytotoxic chemotherapy through whole exome sequencing (WES) of cfDNA. A cohort of 18 lung cancer patients was treated with EGFR TKI or cytotoxic chemotherapy, and a cohort of 37 colorectal cancer patients was treated with EGFR monoclonal antibody or cytotoxic chemotherapy alone. Serum samples were drawn before and after development of drug resistance, and the genetic mutational profile was analyzed with WES data. For 110 paired cfDNA and matched germline DNA WES samples, mean coverage of 138x (range, 52–208.4x) and 47x (range, 30.5–125.1x) was achieved, respectively. After excluding synonymous variants, mutants identified in more than two patients at the time of acquired resistance were selected. Seven genes in lung cancer and 16 genes in colorectal cancer were found, namely, APC, TP53, KRAS, SMAD4, and EGFR. In addition, the GPR155 I357S mutation in lung cancer and ADAMTS20 S1597P and TTN R7415H mutations in colorectal cancer were frequently detected at the time of acquired resistance, indicating that these mutations have an important function in acquired resistance to chemotherapy. Our data suggest that novel genetic variants associated with drug resistance can be identified using cfDNA WES. Further validation is necessary, but these candidate genes are promising therapeutic targets for overcoming drug resistance in lung cancer and colorectal cancer.

Natural products: Potential targets of TME related long non-coding RNAs in lung cancer

Previous studies have shown that PRDX5 and Nrf2 are antioxidant proteins related to abnormal reactive oxidative species (ROS). PRDX5 and Nrf2 play a critical role in the progression of inflammations and tumors. The combination of PRDX5 and Nrf2 was examined by Co-immunoprecipitation, western blotting and Immunohistochemistry. H2O2 was applied to affect the production of ROS and induced multi-resistant protein 1 (MRP1) expression in NSCLC cells. The zebrafish models mainly investigated the synergistic effects of PRDX5 and Nrf2 on lung cancer drug resistance under oxidative stress. We showed that PRDX5 and Nrf2 form a complex and significantly increase the NSCLC tissues compared to adjacent tissues. The oxidative stress improved the combination of PRDX5 and Nrf2. We demonstrated that the synergy between PRDX5 and Nrf2 is positively related to the proliferation and drug resistance of NSCLC cells in the zebrafish models. In conclusion, our data indicated that PRDX5 could bind to Nrf2 and has a synergistic effect with Nrf2. Meanwhile, in the zebrafish models, PRDX5 and Nrf2 have significant regulatory impacts on lung cancer progression and drug resistance activities under oxidative stress.

MALAT1: A key regulator in lung cancer pathogenesis and therapeutic targeting

Lung cancer, one of the leading causes of cancer-related deaths globally, is notorious for its poor prognosis and limited response to conventional therapies. Despite advancements in chemotherapy, targeted therapies, and immunotherapy, the efficacy of these treatments is often undermined by the development of resistance, particularly multidrug resistance (MDR). MDR in lung cancer is primarily driven by various mechanisms, including the overexpression of ATP-binding cassette (ABC) transporters like P-glycoprotein (ABCB1), which actively pump chemotherapeutic drugs out of cancer cells, reducing their intracellular concentration and effectiveness. Additionally, genetic mutations, enhanced DNA repair mechanisms, and alterations in drug targets contribute to this phenomenon. The complexity of MDR not only complicates treatment regimens but also contributes to the high mortality rate associated with lung cancer. Understanding the underlying mechanisms of MDR and developing strategies to overcome this resistance are critical for improving patient outcomes. The objective of this review is to present a comprehensive summary of the current knowledge on conventional and emerging mechanisms of drug resistance, with a particular focus on the involvement of exosomes and exosome-mediated factors that mediate drug resistance in lung cancer. Exosomes, tiny vesicles secreted by cells, play a critical role in drug resistance, especially in lung cancer. They carry genetic material and proteins that can alter the behavior of recipient cells, promoting resistance. In lung cancer, exosomes transfer miRNAs and other molecules that enhance survival pathways and inhibit cell death, contributing to chemoresistance. Recent research highlights the potential of targeting exosomal pathways to develop new therapeutic strategies.

Lung cancer, ranking second globally in both incidence and high mortality among common malignant tumors, presents a significant challenge with frequent occurrences of drug resistance despite the continuous emergence of novel therapeutic agents. This exacerbates disease progression, tumor recurrence, and ultimately leads to poor prognosis. Beyond acquired resistance due to genetic mutations, mounting evidence suggests a critical role of epigenetic mechanisms in this process. Numerous studies have indicated abnormal expression of Histone Methyltransferases (HMTs) in lung cancer, with the abnormal activation of certain HMTs closely linked to drug resistance. HMTs mediate drug tolerance in lung cancer through pathways involving alterations in cellular metabolism, upregulation of cancer stem cell-related genes, promotion of epithelial-mesenchymal transition, and enhanced migratory capabilities. The use of HMT inhibitors also opens new avenues for lung cancer treatment, and targeting HMTs may contribute to reversing drug resistance. This comprehensive review delves into the pivotal roles and molecular mechanisms of HMTs in drug resistance in lung cancer, offering a fresh perspective on therapeutic strategies. By thoroughly examining treatment approaches, it provides new insights into understanding drug resistance in lung cancer, supporting personalized treatment, fostering drug development, and propelling lung cancer therapy into novel territories.

Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge, as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and the encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer, presents novel nanomedicine therapeutics aimed at improving the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for the clinical application of nanomedicine in the management of LC resistance.

BackgroundLung cancer remains the leading cause of cancer-related deaths worldwide, with increasing attention being given to novel therapeutic strategies that target the mechanisms underlying tumor growth and drug resistance. Among these, ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, has become a key focus in cancer research. Despite extensive research, the exact role of ferroptosis in lung cancer progression and treatment remains unclear, especially regarding its interaction with immune cells and the tumor microenvironment.Objective and methodsTo address these limitations, this study utilizes a comprehensive bibliometric analysis to explore the current landscape of ferroptosis research in lung cancer. We collected data from the Web of Science Core Collection, covering articles published between 2015 and 2025, and analyzed them using advanced tools such as VOSviewer and CiteSpace.ResultsThis study uses a comprehensive bibliometric analysis to uncover key trends and emerging areas related to lung cancer in ferroptosis research. Recently, the focus has shifted from basic mechanisms to clinical applications, particularly in developing GPX4-targeted therapies and combination treatments. With increasing international collaboration, the United States and China have become key players. Interdisciplinary research, especially on ferroptosis and the cancer-immune system, offers new insights into its role in the tumor microenvironment and immunotherapy. Ferroptosis shows excellent promise in overcoming drug resistance by regulating iron-dependent lipid peroxidation and enhancing treatment efficacy. Future research should focus on ferroptosis’ clinical translation, particularly in personalized medicine and overcoming resistance, offering broad prospects for lung cancer treatment.ConclusionThis paper provides valuable insights into the trends, key contributors, and emerging frontiers of ferroptosis research in lung cancer. It identifies important developments that can serve as a foundation for translating ferroptosis-based therapies into clinical practice, particularly to address drug resistance in lung cancer.

Lactylation is a newly identified post-translational modification of proteins that occurs in both histones and non-histones. Studies have shown that lactylation plays a key role in the progression of lung cancer (LC) and is associated with poor clinical outcomes. Aberrant histone lactylation can alter gene expression in tumor and immune cells, thereby affecting LC progression and immune suppression. Lactylation of non-histones also plays a role in regulating proliferation and drug resistance in LC. This article provides a brief introduction to lactylation modification, reviews its role and mechanism in the progression and drug resistance of LC, shares the latest research results of lactylation modification in LC, and discusses its potential application in tumor targeted therapy and combined immunotherapy.