Eradicating Drug-tolerant Persister Cells in EGFR-Mutated Non–Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy Simon Baldacci, Elliott J. Brea, Francesco Facchinetti, Zhaorong Li, Kenneth Ngo, et al. Cancer Discovery, 2025 EGFR tyrosine kinase inhibitors have dramatically improved outcomes for patients with EGFR-mutated non–small cell lung cancer (NSCLC), but relapse frequently occurs because of drug-tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. In samples from patients with EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody–drug conjugates (ADC). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo. Treatment with the TROP2 ADC sacituzumab govitecan at the time of osimertinib-induced minimal residual disease only modestly delayed tumor recurrence in vivo, whereas a single infusion of sacituzumab-based TROP2-directed chimeric antigen receptor (CAR) T cells significantly prolonged relapse-free survival, with evidence of cure. These data highlight the potential of engineering TROP2 CAR T-cell therapy to eliminate EGFR DTPs in patients. Significance: We provide a rationale for targeting TROP2 in EGFR-mutated NSCLC DTPs. In contrast to TROP2 ADC therapy, targeting of TROP2 with CAR-T cells can eliminate osimertinib-induced DTPs in vivo, revealing the promise of developing novel TROP2-based CAR-T cells to promote durable response and prevent disease relapse in patients.
Combined standard immunosuppression and immune checkpoint inhibition for BKPyV+ metastatic renal cell carcinoma of the graft in a kidney transplant recipient with chronic rejection: a case report Ilaria Gandolfini, Martina Manini, Giuseppe Daniele Benigno, Micaela Gentile, Alessandra Palmisano, et al. Frontiers in Oncology, 2025 We report on the first case of a dual-kidney transplant recipient diagnosed with a metastatic BK polyomavirus-positive clear renal cell carcinoma with sarcomatoid features, which caused extensive vena cava thrombosis. The patient was successfully treated with the immune checkpoint inhibitors (ICIs) ipilimumab plus nivolumab and continued immunosuppression with tacrolimus, mycophenolate, and steroids. He received ICIs despite the presence of graft dysfunction due to transplant glomerulopathy. As expected, the ICI treatment caused a progressive but asymptomatic decline of the graft function, which resulted in end-stage kidney disease. However, continuation of a full immunosuppression prevented acute rejection, graft intolerance syndrome episodes, or dual graft nephrectomy, which enabled the patient to successfully continue ICIs while on dialysis and to achieve sustained partial remission at the 17-month follow-up.
Genomic and Transcriptomic Profiles in Smokers and Never-Smokers Lung Squamous Cell Carcinoma Patients Matteo Canale, Alessandra Virga, Davide Angeli, Eugenio Fonzi, Letizia Gnetti, et al. Lung Cancer Targets and Therapy, 2025 Purpose Lung Squamous Cell Carcinoma (SCC) is a Non-Small Cell Lung Cancer (NSCLC) subtype with a strong clinical association with smoking habits and a very low incidence in never-smokers. Molecular profiling of SCC in never-smokers could unveil tumor vulnerabilities and new treatment strategies. Patients and Methods We considered a patient cohort of 17 former or current smokers (51.5%) and 16 never-smoker SCC patients (48.5%). TruSight Oncology® 500, investigating hotspots in 523 cancer-related genes, Tumor mutation burden (TMB) and microsatellite instability (MSI), and RNA sequencing was performed on tumor tissue. Genomic and transcriptomic profiles were compared between smokers and never-smoker patients. Results The most frequently altered genes were TP53 (67%), CDKN2A (20%) and PIK3CA (17%), with no substantial differences between groups, except for TP53 which was more frequently mutated in smokers (86.7% vs 46.7%, p = 0.05), who also showed a higher TMB with respect to non-smokers (median 11 mut/Mb vs 5.5 mut/Mb, p = 0.028); all patients were stable for MSI score (median 1.87 vs 1.82, p = 0.87). Activating mutations in EGFR and MET were found in one and two never-smokers, respectively. Three smoker patients had simultaneous amplifications in FGF3, FGF19 and FGF4. Enrichment analyses showed that cyclin-dependent protein Ser/Thr kinase activity and PI3K signaling pathways were affected in both groups, while cellular damage response was exclusively altered in never-smokers. Unsupervised hierarchical clustering on transcriptomes effectively identified different specific transcriptional subtypes between smokers and never-smokers. Gene set enrichment analysis highlighted that tumors from never-smokers are characterized by dysregulation in cell membrane potential and ion homeostasis across cell membrane pathways. Conclusion Genomic and transcriptomic profiles deeply differentiate SCC occurring in never-smokers with respect to SCC in smoker patients. Moreover, SCC could carry canonical NSCLC) activating mutations. Our data suggest that deep molecular analyses resolve tumor heterogeneity and may help with new algorithm-based treatment strategies for SCC.
Multiple targets, germline BRCA1 mutation and HRD in a lung cancer patient: Molecular considerations and treatment decision-making Fabiana Perrone, Francesco Facchinetti, Benedetta Pellegrino, Roberta Minari, Letizia Gnetti, et al. Tumori, 2024 Introduction: Several biomarkers are currently available to address targeted treatments in cancer patients, with lung malignancies representing one of the best examples. Case description: We report the case of a patient affected by advanced non-small cell lung cancer with an uncommon histology and a complex biology. The use of a large next-generation sequencing (NGS) NGS panel allowed us to identify an extremely rare BRAF mutation (V600Q), a MET amplification, a high tumor mutational burden, a germline pathogenetic BRCA1 mutation and a homologous recombination deficiency through RAD51 assay. The treatment decision was driven by the abundance of molecular information. Conclusions: This case highlights that an attentive and critical evaluation of molecular reports is key for the tailoring of treatment algorithms at the patient-level scale.
