biostudies-literatureUnknown27(5)Li SBeijing Municipal Science and Technology CommissionMost advanced colorectal cancer (CRC) patients cannot benefit from targeted therapy due to lack of actionable targets. By mining data from the DepMap, we identified <i>FAM126B</i> as a specific vulnerability in CRC cell lines exhibiting low <i>FAM126A</i> expression. Employing a combination of genetic perturbation and inducible protein degradation techniques, we demonstrate that FAM126A and FAM126B function in a redundant manner to facilitate the recruitment of PI4KIIIα to the plasma membrane for PI4P synthesis. Examination of data from TCGA and GTEx revealed that over 7% of CRC tumor samples exhibited loss of <i>FAM126A</i> expression, contrasting with uniform <i>FAM126A</i> expression in normal tissues. In both CRC cell lines and tumor samples, promoter hypermethylation correlated with tiScience109646https://www.ebi.ac.uk/biostudies/studies/S-EPMC11025007biostudies-literatureFrequent loss of <i>FAM126A</i> expression in colorectal cancer results in selective <i>FAM126B</i> dependency.PMC11025007Li SHan TfalseFrequent loss of <i>FAM126A</i> expression in colorectal cancer results in selective <i>FAM126B</i> dependency.Most advanced colorectal cancer (CRC) patients cannot benefit from targeted therapy due to lack of actionable targets. By mining data from the DepMap, we identified <i>FAM126B</i> as a specific vulnerability in CRC cell lines exhibiting low <i>FAM126A</i> expression. Employing a combination of genetic perturbation and inducible protein degradation techniques, we demonstrate that FAM126A and FAM126B function in a redundant manner to facilitate the recruitment of PI4KIIIα to the plasma membrane for PI4P synthesis. Examination of data from TCGA and GTEx revealed that over 7% of CRC tumor samples exhibited loss of <i>FAM126A</i> expression, contrasting with uniform <i>FAM126A</i> expression in normal tissues. In both CRC cell lines and tumor samples, promoter hypermethylation correlated with t2024-01-01T00:00:00Z2024 May2026-05-29T09:45:02.024Z2025-07-27T03:11:10.489ZS-EPMC110250073863856610.1016/j.isci.2024.109646