Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors

Area of Science:

• Oncology
• Cancer Genetics
• Molecular Therapeutics

Background:

• Aneuploidy, specifically copy number gains of chromosome 8 (chr8), is common in various cancers, including malignant peripheral nerve sheath tumors (MPNSTs).
• MPNSTs are aggressive sarcomas often associated with Neurofibromatosis type 1 (NF1) and characterized by ERK pathway hyperactivation.

Purpose of the Study:

• To investigate the role of chr8 gain in MPNST pathogenesis.
• To evaluate focal adhesion kinase (FAK) as a therapeutic target in MPNSTs.
• To assess the efficacy of FAK inhibitors (FAKi) alone and in combination with RAF/MEK inhibitors (RAF/MEKi).

Main Methods:

• CRISPR knockout screen to identify essential genes on chr8 in MPNSTs.
• Pharmacological and genetic inhibition of FAK.
• In vitro and in vivo studies using MPNST cell lines and patient-derived xenograft (PDX) models.
• Combination therapy with FAKi and RAF/MEKi.

Main Results:

• Identified 58 essential genes on chr8, including PTK2 (encoding FAK).
• FAK inhibition reduced MPNST cell proliferation and tumor growth.
• Combined FAKi and RAF/MEKi treatment enhanced apoptosis and suppressed key signaling pathways (FAK, STAT3, AKT).
• Combination therapy demonstrated superior efficacy in chr8 gain MPNST-PDX models.

Conclusions:

• FAK is a crucial target in chr8 gain-driven MPNSTs.
• Co-targeting FAK/RAF/MEK represents a promising therapeutic strategy for chr8 gain MPNSTs and related cancers.
• Combination therapy offers superior tumor growth inhibition, particularly in MPNSTs with chromosome 8 copy number gains.