Front Cell Dev Biol. 2026 Aug 24;14:1867246. doi: 10.3389/fcell.2026.1867246. eCollection 2026.

ABSTRACT

Acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a formidable challenge in the treatment of non-small cell lung cancer (NSCLC). Despite the remarkable efficacy of these agents, resistance inevitably develops, typically within approximately 10 months of treatment initiation. This review elucidates the multifaceted mechanisms driving this resistance, broadly categorized into on-target EGFR-dependent alterations and off-target EGFR-independent bypass pathway activations. On-target mechanisms include the emergence of tertiary EGFR mutations, most notably C797S, which disrupts TKI binding. Off-target mechanisms encompass the activation of alternative signaling pathways such as MET and HER2/HER3 amplification, as well as histological transformations and complex changes within the tumor microenvironment. Furthermore, recent discoveries highlight the role of epigenetic dysregulation and metabolic reprogramming in fostering resistance. To counter this pervasive adaptability, advanced diagnostic methodologies, including liquid biopsy and high-resolution omics technologies, are crucial for real-time molecular profiling. The field is actively exploring emerging combination therapeutic strategies to circumvent these diverse resistance pathways, aiming to prolong clinical benefits and improve patient outcomes. The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.

PMID:42707604 | PMC:PMC13547778 | DOI:10.3389/fcell.2026.1867246

Food Funct. 2026 Mar 31. doi: 10.1039/d5fo04958j. Online ahead of print.

ABSTRACT

The probiotic yeast Saccharomyces boulardii is renowned for its clinical efficacy, which is intrinsically linked to its exceptional ability to survive the harsh gastrointestinal (GI) environment. However, a comprehensive understanding of the molecular mechanisms and regulatory pathways underlying the stress tolerance of S. boulardii remains limited. This study employed an integrated transcriptomic and proteomic approach to systematically map the dynamic responses of S. boulardii to simulated GI transit. Our analysis revealed that the intestinal phase posed a significantly greater challenge than the gastric phase, triggering extensive molecular reprogramming. A core adaptive strategy was the marked upregulation of the central carbon metabolism, particularly glycolysis, as evidenced by the concerted overexpression of key enzymes at both transcriptional and translational levels, indicating a heightened demand for energy to fuel stress defence mechanisms. Furthermore, significant enrichment was observed in the pathways related to nitrogen and fatty acid metabolism. Integration of the multi-omics datasets highlighted the complexity of the regulatory response, with frequent discordance between mRNA and protein abundance underscoring the importance of post-transcriptional regulation. This study provides a detailed molecular profile of the stress tolerance network in S. boulardii, elucidating the strategic metabolic rewiring and multi-layered regulation that underpin its probiotic resilience. The findings offer valuable insights and a foundational resource for the future development of enhanced probiotic therapies.

PMID:41914832 | DOI:10.1039/d5fo04958j