Maritoclax Overcomes FBW7 Deficiency-Driven Irinotecan Resistance in Colorectal Cancer by Targeting MCL1.

ABSTRACT:

Introduction

FBW7, a tumor suppressive E3 ubiquitin ligase frequently mutated in colorectal cancer (CRC), mediates chemotherapy resistance. While irinotecan (via its active metabolite SN38) is a first-line TOP1 inhibitor for advanced CRC, the mechanistic link between FBW7 dysfunction and irinotecan resistance remains elusive.

Methods

CRISPR/Cas9 gene editing and RNA interference were applied to establish FBW7-knockout and -knockdown CRC cells. CCK8 assay was performed to detect the inhibition ratio of SN38 and Maritoclax on CRC cells. Western blot, immunochemistry, RT-qPCR and co-immunoprecipitation were performed to detect the expression and interaction of FBW7 and MCL1. The conformational change of the FBW7 R465C mutation and its interaction with substrates were elucidated

SUBMITTER: Lin Q 

PROVIDER: S-EPMC12661461 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature