Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is often linked to tumor metastasis, making control of metastasis crucial. Here, we identified a critical signaling hub responsible for cancer metastasis and resistance development: mitochondrial cristae remodeling and metabolic reprogramming, using an anoikis-resistant cell model and a mouse tail vein metastasis model. EGFR-TKI-resistant cells exhibited stronger anoikis resistance (AR) and mitochondrial metabolism compared with sensitive cells, making them more prone to metastasis.

Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard treatments for EML4-ALK-positive NSCLC, but resistance to these agents remains a challenge. This study aimed to determine the mechanisms of acquired resistance to the third-generation ALK-TKI lorlatinib.

Multieffect Specific Nanovesicles for Homing Resistant Tumors and Overcoming Osimertinib-Acquired Resistance in NSCLC.

Acquired resistance to osimertinib (Osi) remains a major obstacle in the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). AXL elevation is a known key mechanism of Osi-resistance, and therapeutic strategies remain scarce. Emerging evidence reveals that an increased intracellular glutathione (GSH) level induces Osi resistance.

Neutrophil extracellular traps in tumor metabolism and microenvironment.

Neutrophil extracellular traps (NETs) are intricate, web-like formations composed of DNA, histones, and antimicrobial proteins, released by neutrophils. These structures participate in a wide array of physiological and pathological activities, including immune rheumatic diseases and damage to target organs. Recently, the connection between NETs and cancer has garnered significant attention.

AXL: shapers of tumor progression and immunosuppressive microenvironments.

As research progresses, our understanding of the tumor microenvironment (TME) has undergone profound changes. The TME evolves with the developmental stages of cancer and the implementation of therapeutic interventions, transitioning from an immune-promoting to an immunosuppressive microenvironment. Consequently, we focus intently on the significant role of the TME in tumor proliferation, metastasis, and the development of drug resistance.

Metformin promotes anti-tumor immunity in mutant NSCLC through AXIN1-dependent upregulation of multiple nucleotide metabolites.

Background: Metformin has pleiotropic effects beyond glucose reduction, including tumor inhibition and immune regulation. It enhanced the anti-tumor effects of programmed cell death protein 1 (PD-1) inhibitors in serine/threonine kinase 11 ( mutant non-small cell lung cancer (NSCLC) through an axis inhibition protein 1 (AXIN1)-dependent manner. However, the alterations of tumor metabolism and metabolites upon metformin administration remain unclear.

Mesoporous manganese nanocarrier target delivery metformin for the co-activation STING pathway to overcome immunotherapy resistance.

Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use.

Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.

In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation.

Sialyltransferase ST3GAL4 confers osimertinib resistance and offers strategies to overcome resistance in non-small cell lung cancer.

The third-generation EGFR-TKI osimertinib is widely used in EGFR-mutated positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. The currently known mechanisms only explain resistance in a small proportion of patients. For most patients, the mechanism of osimertinib resistance is still unclear, especially for EGFR-independent resistance.

Overall signature of acquired KRAS gene changes in advanced non-small cell lung cancer patient with EGFR-TKI resistance.

Objective: Numerous scattered case studies continue to demonstrate a strong correlation between acquired KRAS mutations and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in non-small cell lung cancer. However, the comprehensive understanding of the KRAS pathway following the failure of epidermal growth factor receptor-tyrosine kinase inhibitor therapy remains limited.

Methods: We conducted a retrospective evaluation of the next generation sequencing data from 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations after experiencing progression with epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Predictive value of early kinetics of ctDNA combined with cfDNA and serum CEA for EGFR-TKI treatment in advanced non-small cell lung cancer.

Background: Circulating tumor DNA (ctDNA) has made a breakthrough as an early biomarker in operable early-stage cancer patients. However, the function of ctDNA combined with cell-free DNA (cfDNA) as a predictor in advanced non-small cell lung cancer (NSCLC) remains unknown. Here, we explored its potential as a biomarker for predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced NSCLC.

pH-responsive theranostic nanoplatform of ferrite and ceria co-engineered nanoparticles for anti-inflammatory.

Multiple component integration to achieve both therapy and diagnosis in a single theranostic nanosystem has aroused great research interest in the medical investigator. This study aimed to construct a novel theranostic nanoplatform ferrite and ceria co-engineered mesoporous silica nanoparticles (Fe/Ce-MSN) antioxidant agent though a facile metal Fe/Ce-codoping approach in the MSN framework. The resulted Fe-incorporated ceria-based MSN nanoparticles possessing a higher Ce-to-Ce ratio than those revealed by ceria-only nanoparticles.

Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC.

Lorlatinib is a promising third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that has been approved for treating ALK-positive non-small-cell lung cancer (NSCLC) patients with previous ALK-TKI treatment failures. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A more comprehensive understanding of the acquired resistance mechanisms to lorlatinib will enable the development of more efficacious therapeutic strategies.

Metformin Combining PD-1 Inhibitor Enhanced Anti-Tumor Efficacy in Mutant Lung Cancer Through AXIN-1-Dependent Inhibition of STING Ubiquitination.

Non-small-cell lung cancer (NSCLC) with mutation showed primary resistance to immune checkpoint inhibitors (ICIs). The glucose-lowering drug metformin exerted anti-cancer effect and enhanced efficacy of chemotherapy in NSCLC with co-mutation, yet it is unknown whether metformin may enhance ICI efficacy in mutant NSCLC. We studied the impact of metformin on ICI efficacy in mutant NSCLC and using colony formation assay, cell viability assay, Ki67 staining, ELISA, CRISPR/Cas9-mediated knockout, and animal experiments.