Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment

Area of Science:

• Oncology
• Hepatology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) associated with Hepatitis B virus (HBV) often involves TSC2 inactivation, leading to mTOR pathway activation.
• This TSC2-deficient HCC subtype exhibits aggressive behavior, early recurrence post-hepatectomy, and limited response to sorafenib.
• Sorafenib, a targeted therapy for advanced HCC, shows reduced efficacy in HBV-positive patients.

Purpose of the Study:

• To elucidate the mechanisms of sorafenib resistance in mTOR-activated, TSC2-deficient HBV-associated HCC.
• To identify potential therapeutic strategies to overcome sorafenib resistance in this specific liver cancer subtype.

Main Methods:

• Investigated the role of mTOR activation (due to TSC2 or PTEN loss) in sorafenib insensitivity.
• Examined the molecular mechanism involving HSP70, CREB1, CREBBP, and SESN3 in conferring sorafenib resistance.
• Assessed the synergistic effect of pifithrin-μ (HSP70 inhibitor) and sorafenib in preclinical models.

Main Results:

• mTOR-activated cells, resulting from TSC2 or PTEN loss, demonstrated resistance to sorafenib.
• HSP70 was found to enhance the interaction between mTOR-activated CREB1 and CREBBP, upregulating SESN3 transcription.
• Elevated SESN3 levels increased cellular antioxidant capacity, contributing to sorafenib resistance.
• Pifithrin-μ combined with sorafenib induced ferroptosis and suppressed tumor growth in TSC2-deficient HCC models.

Conclusions:

• The mTOR-CREB1-SESN3 signaling axis plays a critical role in mediating sorafenib resistance in liver cancer.
• Targeting HSP70 with pifithrin-μ in combination with sorafenib represents a promising therapeutic approach for mTOR-activated HCC.
• These findings offer a new strategy for treating aggressive, TSC2-deficient HBV-associated liver cancer.