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Background: The molecular non-genetic changes of resistance to sotorasib are currently uncertain. The aim of this study was to generate a sotorasib-resistant cell line via selective pressure and systematically examine the molecular and phenotypic alterations caused by resistance., Methods: Mutant NCI-H358 (KRAS G12C ) were exposed to incremental doses (2-512 nM) of sotorasib. Then, resistant clones were separated by single-cell sorting. Proliferation was analyzed in real-time by xCELLigence; protein profiles were quantified by protein arrays; and mRNA expression profile was measured using the PanCancer Pathways panel by NanoString. In silico analyses were conducted from a database comprising patient-derived xenograft (PDX) models and cell lines resistant to sotorasib. AKT and p38. The synergistic effect of combining AKT, p38, and EGFR inhibitors was assessed using the SynergyFinder platform. Additionally, AKT and p38 genes were silenced using esiRNA., Results: Sotorasib-resistant H358-R cell line displayed markers of the mesenchymal-epithelial transition and loss of cell adhesion. Were identified 30 overexpressed genes in the resistance model, implicating in signaling pathways that leads to AKT activation and heightened protein expression levels of phosphorylated AKT and p38. To identify potential therapeutic strategies for overcoming sotorasib resistance, we investigated the combination of AKT and p38 inhibitors. Notably, combined inhibition of AKT (MK2206) and p38 (adezmapimod) restored sensitivity to sotorasib in resistant cell lines, as did silencing AKT expression., Conclusion: These findings underscore the importance of adaptive mechanisms in sotorasib resistance in NSCLC cells contributing by EMT activation and demonstrates synergic combination with AKT and p38 inhibitors to restore sotorasib sensitivity in KRAS G12C cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Megid, Ribeiro, Gomes, Laus, Ferro Leal, Sussuchi da Silva, Ariwoola, Dias, Reis and Jose da Silva-Oliveira.)

These days, cancer is thought to be more than just one illness, with several complex subtypes that require different screening approaches. These subtypes can be distinguished by the distinct markings left by metabolites, proteins, miRNA, and DNA. Personalized illness management may be possible if cancer is categorized according to its biomarkers. In order to stop cancer from spreading and posing a significant risk to patient survival, early detection and prompt treatment are essential. Traditional cancer screening techniques are tedious, time-consuming, and require expert personnel for analysis. This has led scientists to reevaluate screening methodologies and make use of emerging technologies to achieve better results. Using time and money saving techniques, these methodologies integrate the procedures from sample preparation to detection in small devices with high accuracy and sensitivity. With its proven potential for biomedical use, surface-enhanced Raman scattering (SERS) has been widely used in biosensing applications, particularly in biomarker identification. Consideration was given especially to the potential of SERS as a portable clinical diagnostic tool. The approaches to SERS-based sensing technologies for both invasive and non-invasive samples are reviewed in this article, along with sample preparation techniques and obstacles. Aside from these significant constraints in the detection approach and techniques, the review also takes into account the complexity of biological fluids, the availability of biomarkers, and their sensitivity and selectivity, which are generally lowered. Massive ways to maintain sensing capabilities in clinical samples are being developed recently to get over this restriction. SERS is known to be a reliable diagnostic method for treatment judgments. Nonetheless, there is still room for advancement in terms of portability, creation of diagnostic apps, and interdisciplinary AI-based applications. Therefore, we will outline the current state of technological maturity for SERS-based cancer biomarker detection in this article. The review will meet the demand for reviewing various sample types (invasive and non-invasive) of cancer biomarkers and their detection using SERS. It will also shed light on the growing body of research on portable methods for clinical application and quick cancer detection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

NTRK1, 2, and 3 fusions are important therapeutic targets for NSCLC patients, but their prevalence in South American admixed populations needs to be better explored. NTRK fusion detection in small biopsies is a challenge, and distinct methodologies are used, such as RNA-based next-generation sequencing (NGS), immunohistochemistry, and RNA-based nCounter. This study aimed to evaluate the frequency and concordance of positive samples for NTRK fusions using a custom nCounter assay in a real-world scenario of a single institution in Brazil. Out of 147 NSCLC patients, 12 (8.2%) cases depicted pan-NTRK positivity by IHC. Due to the absence of biological material, RNA-based NGS and/or nCounter could be performed in six of the 12 IHC-positive cases (50%). We found one case exhibiting an NTRK1 fusion and another an NTRK3 gene fusion by both RNA-based NGS and nCounter techniques. Both NTRK fusions were detected in patients diagnosed with lung adenocarcinoma, with no history of tobacco consumption. Moreover, no concomitant EGFR, KRAS, and ALK gene alterations were detected in NTRK-positive patients. The concordance rate between IHC and RNA-based NGS was 33.4%, and between immunohistochemistry and nCounter was 40%. Our findings indicate that NTRK fusions in Brazilian NSCLC patients are relatively rare (1.3%), and RNA-based nCounter methodology is a suitable approach for NRTK fusion identification in small biopsies., (© 2023. The Author(s).)

Introduction: TP53 is the most frequently mutated gene in lung tumors, but its prognostic role in admixed populations, such as Brazilians, remains unclear. In this study, we aimed to evaluate the frequency and clinicopathological impact of TP53 mutations in non-small cell lung cancer (NSCLC) patients in Brazil., Methods: We analyzed 446 NSCLC patients from Barretos Cancer Hospital. TP53 mutational status was evaluated through targeted next-generation sequencing (NGS) and the variants were biologically classified as disruptive/nondisruptive and as truncating/nontruncating. We also assessed genetic ancestry using 46 ancestry-informative markers. Analysis of lung adenocarcinomas from the cBioportal dataset was performed. We further examined associations of TP53 mutations with patients' clinicopathological features., Results: TP53 mutations were detected in 64.3% (n = 287/446) of NSCLC cases, with a prevalence of 60.4% (n = 221/366) in lung adenocarcinomas. TP53 mutations were associated with brain metastasis at diagnosis, tobacco consumption, and higher African ancestry. Disruptive and truncating mutations were associated with a younger age at diagnosis. Additionally, cBioportal dataset revealed that TP53 mutations were associated with younger age and Black skin color. Patients harboring disruptive/truncating TP53 mutations had worse overall survival than nondisruptive/nontruncating and wild-type patients., Conclusion: TP53 mutations are common in Brazilian lung adenocarcinomas, and their biological characterization as disruptive and truncating mutations is associated with African ancestry and shorter overall survival., (© 2023 S. Karger AG, Basel.)

Background: Microsatellite instability (MSI) in non-small cell lung cancer (NSCLC) is uncommon; however, most studies refer to European and Asian populations. There are currently no data on MSI frequency in highly admixed populations, such as the one represented by Brazilian NSCLC patients., Aim: This study aimed to evaluate the frequency of MSI in Brazilian NSCLC patients., Methods: We evaluated 526 patients diagnosed with NSCLC at the Barretos Cancer Hospital (Brazil). The molecular MSI evaluation was performed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. The mutation profile of MSI-positive cases was performed using next-generation sequencing., Results: Only 1 patient was MSI positive (0.19%). This patient was a female, white, and active smoker, and she was diagnosed with clinical stage IV lung adenocarcinoma at 75 years old. The molecular profile exhibited 4 Tumor Protein p53 (TP53) mutations and the absence of actionable mutations in the Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), or V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) genes., Conclusions: The frequency of MSI in Brazilian NSCLC patients is equally rare, a finding that is consistent with the current literature based on other populations such as Europeans, North Americans, and Asians., (© 2021 S. Karger AG, Basel.)