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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• FBW7 is a tumor suppressor frequently mutated in colorectal cancer (CRC).
• FBW7 dysfunction is linked to chemotherapy resistance, but the mechanism for irinotecan resistance is unclear.
• Irinotecan (SN38) is a key treatment for advanced CRC.

Purpose of the Study:

• Investigate the mechanistic link between FBW7 deficiency and irinotecan resistance in CRC.
• Determine if MCL1 inhibition can overcome irinotecan resistance in FBW7-deficient CRC.
• Evaluate the therapeutic potential of combining Maritoclax and irinotecan.

Main Methods:

• Utilized CRISPR/Cas9 and RNA interference to create FBW7-deficient CRC models.
• Assessed cell viability, protein expression (Western blot, IHC), and gene expression (RT-qPCR).
• Investigated protein interactions (co-IP), modeled mutation effects (AlphaFold), and performed in vivo xenograft studies.

Main Results:

• FBW7 deficiency, mutations, or low expression correlated with increased MCL1 and reduced SN38 sensitivity in CRC.
• The FBW7 R465C mutation impaired FBW7-MCL1 binding, stabilizing MCL1 and conferring SN38 resistance.
• Maritoclax, an MCL1 inhibitor, reversed irinotecan resistance in FBW7-deficient cells and xenografts, showing synergy with irinotecan.

Conclusions:

• FBW7 deficiency drives irinotecan resistance through MCL1 stabilization.
• MCL1 inhibition represents a viable therapeutic strategy for FBW7-deficient CRC.
• Combination therapy with Maritoclax and irinotecan shows promise for clinical translation.