Genomic characteristics of PD-L1-Induced resistance to EGFR-TKIs in lung adenocarcinoma

The co-occurrence of PD-L1 positivity and EGFR mutations in advanced NSCLC often limits EGFR-TKIs effectiveness, with unclear mechanisms. We analyzed 103 treatment-naive EGFR-mutant LUAD patients from three centers, assessing PD-L1 expression and performing NGS analysis. SMO mutations and MET amplification were significantly higher in the PD-L1 ≥ 1% group versus PD-L1 &lt; 1% group (SMO: 8% vs. 0%, <i>p</i> = 0.048; MET: 18% vs. 7%, <i>p</i> = 0.023). The DNA Damage Response and Repair (DDR) pathogenic deficiency mutations, along with biological processes and signaling pathways related to DNA recombination, cell cycle transition and abnormal phosphorylation, were more prevalent in the PD-L1 ≥ 1% group. PIK3CA and RARA clonal alterations were more common in PD-L1 &lt; 1% group, while TP53 clonal mutations predominated in PD-L1 ≥ 1% group. Retrospective analysis showed EGFR-TKIs plus chemotherapy extended median PFS by 9.8 months, potentially overcoming EGFR-TKI monotherapy resistance. This study elucidates the genomic characteristics of PD-L1-induced resistance to EGFR-TKIs. For patients with concurrent mutations in EGFR and PD-L1 expression, a first-line treatment strategy combining EGFR-TKIs with chemotherapy may offer a more effective alternative. This study looked at lung cancer patients who have two important characteristics: changes in a gene called EGFR and a protein called PD-L1. While there are drugs (EGFR-TKIs) that target EGFR mutations, they don’t always work well when PD-L1 is also present. The researchers studied 103 lung cancer patients to understand why this happens. They found that patients with higher PD-L1 levels had different genetic patterns, including more changes in genes that affect DNA repair and cell growth. Importantly, they discovered that combining standard EGFR-targeting drugs with chemotherapy helped patients respond better to treatment, extending the time before their cancer got worse by almost 10 months. This suggests that patients with both EGFR mutations and PD-L1 might benefit more from a combination treatment approach rather than using EGFR-targeting drugs alone.