FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Heat shock protein 90 (Hsp90) is overexpressed in cancers and crucial for malignant phenotypes.
• Hsp90 inhibition shows promise by inducing tumor cell death via client oncoprotein degradation.
• The precise mechanisms of Hsp90 inhibitor-induced cell death and resistance biomarkers are not fully understood.

Purpose of the Study:

• To elucidate the mechanism of Hsp90 inhibitor-induced colorectal cancer cell death.
• To identify biomarkers predicting sensitivity or resistance to Hsp90 inhibitors.
• To investigate the role of FBW7 and Mcl-1 in Hsp90 inhibitor response.

Main Methods:

• Utilized colorectal cancer cell lines with varying FBW7 mutational status.
• Assessed Mcl-1 protein levels and degradation pathways.
• Investigated the role of GSK3β phosphorylation in Mcl-1 regulation.
• Employed genetic manipulation (knock-in) to block Mcl-1 phosphorylation.
• Evaluated sensitivity to Hsp90 inhibitors in vitro and in vivo.
• Tested efficacy of Mcl-1-selective inhibitors.

Main Results:

• Colorectal cancer cells with inactivating FBW7 mutations are intrinsically resistant to Hsp90 inhibitors.
• Resistance is linked to the lack of Mcl-1 degradation.
• Hsp90 inhibition triggers GSK3β-dependent Mcl-1 phosphorylation, leading to FBW7 binding, ubiquitination, and degradation.
• Blocking Mcl-1 phosphorylation confers resistance to Hsp90 inhibitors.
• Mcl-1-selective inhibitors can overcome this resistance.

Conclusions:

• GSK3β/FBW7-dependent Mcl-1 degradation is critical for Hsp90 inhibitor efficacy in colorectal cancer.
• FBW7 mutational status serves as a potential predictive biomarker for Hsp90-targeted therapy.
• Targeting Mcl-1 offers a therapeutic strategy for Hsp90 inhibitor-resistant colorectal cancers.