Fig. 6.

High frequency of EpCAM mutations in NSCLC suggests roles in tumorigenesis and drug sensitivity. A-B Analysis of metastatic lung cancer patients indicates that EpCAM mutations do not significantly alter overall survival. C-D The GENIE cohort dataset reveals that NSCLC has the highest frequency of EpCAM mutations. These mutations are predominantly associated with cancers harboring mutations in TP53, KRAS, EGFR, KEAP1, and LKB1. E Stable EpCAM mutations were expressed in A549 cells. SRE reporter assay (measuring ERK activity, see methods) shows that introducing EpCAM mutations increased ERK activity. F In loss-of-function models, NSCLC cell lines (A549, H1299, H460, H226, and H23) expressing EpCAM mutations demonstrate increased cell death. G Stable A549 cells treated with Trametinib for 72 h. For treatment, cell lines were treated with 200–500-nM Trametinib for 72 h. Cell death was monitored by annexin-V staining. H. Structural disruption of EpCAM due to somatic mutation drives aberrant ERK pathway activation, resulting in enhanced cellular proliferation. Pharmacologic inhibition of MEK presents a rational therapeutic strategy to counteract this oncogenic signaling cascade