Druggable genetic targets in endometrial cancer^✰,✰✰

FBXW7 is frequently somatically mutated in grade 3 endometrioid endometrial cancers (G3EECs) and serous endometrial cancers (SECs), high-risk cancers associated with poor prognosis. CRISPR-edited cell lines identified the proteomic and phosphoproteomic effects of FBXW7 mutation in 3 high-risk endometrial cancers (ECs), including altered protein levels of L1CAM and TGM2. This result is important because L1CAM and TGM2 are druggable proteins that could represent new therapeutic targets.

We used cBioPortal for Cancer Genomics to analyze data in The Cancer Genome Atlas (TCGA). We used the UCSC Xena Browser to analyze gene expression. For differential gene expression analysis, the gene ontology molecular function 2018 version was used. The analysis was focused on determined genes.

FBXW7 mutations affect gene expression of L1CAM but are unrelated to TGM2 gene expression. L1CAM gene expression is significantly related to survival. Patients with lower L1CAM gene expression have better survival. FBXW7 mutations are unrelated to survival. TGM2 gene expression is unrelated to FBXW7 mutations. TGM2 gene expression is unrelated to survival, all tumor grades or grade 3 alone.

We agree with Urick et al. that L1CAM may be a promising druggable target in endometrial carcinoma. The lack of relationship of TGM2 expression with FBXW7 mutations and endometrial cancer survival suggests that TGM2 might not be of as much value as a druggable target, compared to L1CAM. However, the fact that a certain alteration is not prognostic for cancer survival does not necessarily mean that the alteration will not be targetable. More data, such as inhibition of each gene by calculating drug targetability, may be required to support this conclusion.