Jinjing Xia

Third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) is the standard therapy for patients harboring T790M after first‐generation EGFR‐TKI resistance. However, the impact of acquired EGFR amplification on the efficacy of third‐generation EGFR‐TKI against T790M remains uncertain. We aimed to investigate whether the presence of acquired EGFR amplification after first‐generation EGFR‐TKI resistance influences the efficacy of third‐generation EGFR‐TKI in patients with advanced non‐small‐cell lung cancer (NSCLC). We reviewed data from 275 advanced NSCLC patients harboring T790M after first‐generation EGFR‐TKI resistance. Patients were categorized into two groups based on the presence or absence of acquired EGFR amplification identified through next‐generation sequencing (NGS) after first‐line EGFR‐TKI treatment. We evaluated the efficacy of osimertinib used as a second‐line treatment. Among these patients, 59 exhibited acquired EGFR amplification, while 216 did not. The median progression‐free survival (PFS) was 12.20 months in the EGFR amplification group and 12.03 months in the non‐amplification group (p = 0.011), with median overall survival (OS) of 33.90 months and 23.30 months, respectively (p = 0.164). Multivariate analysis of PFS revealed that acquired EGFR amplification and EGFR 19del were independent prognostic factors for patients with T790M undergoing osimertinib. Additionally, subgroup analysis indicated a prolonged PFS in patients with EGFR 19del compared to those with EGFR 21L858R (p = 0.034) in the EGFR amplification group. Following first‐generation EGFR‐TKI resistance, advanced EGFR‐mutant NSCLC patients harboring both acquired T790M and EGFR amplification are likely to experience enhanced PFS with osimertinib. This phenomenon is particularly noteworthy among individuals with EGFR 19del.

YAP is a transcriptional co-activator with critical roles in tumorigenesis. However, its upstream regulatory mechanism, especially how its mRNA stability is regulated, remains to be further studied. Here, we validated that YAP expression was higher in lung adenocarcinoma (LUAD) tissues compared to adjacent normal tissues, and found that YAP m⁵C modification occurred in its 328–331 3′ UTR region under the promotion NSUN2 and ALYREF, and increased the stability of YAP mRNA. This m⁵C modification also inhibited miR-582-3p binding and m⁶A modification in the nearby region. In addition, YAP m⁵C modification enhanced the exosome secretion effect, which was caused by two YAP-dependent transcription factors, Mycn and SOX10, and then stimulating the transcription of seven downstream exosome-promoting genes. Furthermore, we found that YAP m⁵C modification and its exosome-secretion-promoting function contributed to the malignant phenotype and AZD9291 (a third-generation EGFR-TKI) resistance of LUAD cells. Collectively, YAP is promoted by its m⁵C modification, and blocking YAP m⁵C modification will be helpful for future LUAD treatment.