CHEK1 is a synthetic lethal interactor of FBXO7 in colonic epithelial cells

Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, with chromosome instability (CIN) present in approximately 85% of cases and associated with poor prognosis. Reduced expression of FBXO7, a component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex, occurs in about one-third of CRCs and correlates with CIN, positioning FBXO7 as a potential therapeutic target. This study employed bioinformatics analyses, small interfering RNA (siRNA) screening, small molecule inhibition, and quantitative imaging (QuantIM) microscopy to identify synthetic lethal interactors of FBXO7. Shallow deletions of FBXO7 in CRC patient samples was found to associate with decreased gene expression and adverse clinical outcomes. Targeted silencing or pharmacological inhibition of CHEK1 using Prexasertib significantly reduced proliferation in FBXO7-deficient cells. Mechanistic studies revealed that Prexasertib treatment increased DNA double-strand breaks and apoptosis specifically in FBXO7-deficient cells. Furthermore, combining Prexasertib with 5-fluorouracil, a standard chemotherapeutic agent, produced a synergistic killing effect. These findings establish a novel synthetic lethal relationship between FBXO7 and CHEK1, suggesting that CHEK1 inhibition may provide a targeted therapeutic strategy for CRC patients with FBXO7 deficiencies, and highlighting the broader potential of exploiting SCF complex alterations in CRC therapy.