Autophagy inhibition overcomes sorafenib resistance in S45F-mutated desmoid tumors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Desmoid tumors (DTs) are rare, locally invasive fibroblastic lesions with significant morbidity.
• Current treatment options for DTs are limited, highlighting the need for novel therapeutic strategies.
• Sorafenib shows promise, prompting a phase 3 clinical trial and necessitating a deeper understanding of its mechanism.

Purpose of the Study:

• To investigate the efficacy of sorafenib in desmoid tumor cells.
• To identify mechanisms underlying differential responses to sorafenib based on specific mutations.
• To explore combination therapies for enhancing sorafenib effectiveness in resistant DT subtypes.

Main Methods:

• Comprehensive analysis of sorafenib efficacy across a large panel of desmoid cell strains.
• Clustering analysis to identify distinct responder groups based on mutation status (CTNNB1).
• Investigation of autophagy pathways and their role in sorafenib resistance, including genetic and pharmacological inhibition.

Main Results:

• Distinct higher- and lower-responder DT cell groups were identified.
• CTNNB1 mutation status was a key determinant of sorafenib response.
• S45F-mutated DTs exhibited resistance to sorafenib, dependent on autophagy for survival.
• Inhibition of autophagy restored sorafenib sensitivity in S45F-mutated DT cells.
• Sorafenib effectively inhibited wild-type and T41A-mutated DT cells, inducing apoptosis.

Conclusions:

• Sorafenib response in desmoid tumors is mutation-dependent, with S45F mutations conferring resistance.
• Autophagy inhibition can overcome sorafenib resistance in S45F-mutated DTs.
• Combination therapy with hydroxychloroquine and sorafenib enhances anti-tumor effects in S45F-mutated DTs.
• Profiling CTNNB1 mutation status may guide clinical decisions for sorafenib treatment in desmoid patients.