High PER1 expression is associated with STK11 mutation and clinical biomarkers of immunotherapy resistance in lung adenocarcinoma.

AIM: This study characterizes the functional effects and clinical characteristics of high PER1 mRNA and high PER1 protein expression in treatment resistant lung adenocarcinoma. METHODS: HBEC3-KT cells were modified by STK11 CRISPR knockout and A549 cells by LKB1 addback using stable transfection. RNA sequencing and western blot were used to profile gene and protein expression. Pooled siRNA knockdown of PER1 was used to assess impacts on cell proliferation and 3D invasion. Human lung adenocarcinoma data were analyzed using cBioPortal. RESULTS: PER1 mRNA and protein are upregulated in STK11-mutant lung adenocarcinoma tumors and STK11-knockout human bronchial epithelial cells (HBEC3-KT). Addback of wildtype LKB1 in A549 lung cancer cells is sufficient to decrease PER1 protein levels. Knockdown of PER1 decreased cell growth, proliferation, and 3D invasion in LKB1-deficient cell models. High PER1 expression in lung cancer patients correlates with LKB1 mutation status, decreased expression of the gene that encodes PD-L1, and altered hypoxia and immune and stromal ESTIMATE scores. CONCLUSION: PER1 has oncogenic activity in LKB1-mutant lung cancer cells and high PER1 expression in lung adenocarcinoma patients may represent an independent biomarker of resistance to immunotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-025-06269-9.