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

NF1-deficient tumours show ERK pathway hyperactivation; chromosome 8 gain creates dependency on essential genes including PTK2, encoding focal adhesion kinase (FAK), producing a dual FAK and RAF/MEK vulnerability.

Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive sarcomas frequently linked to the neurofibromatosis type 1 (NF1) cancer predisposition syndrome, and chromosome 8 gain is recurrent in them. A CRISPR knockout screen identified 58 essential genes on chromosome 8, including PTK2, which encodes focal adhesion kinase (FAK). Both pharmacological and genetic FAK inhibition reduced MPNST cell proliferation in vitro and tumour growth in vivo; combining a FAK inhibitor with a RAF/MEK inhibitor further suppressed phosphorylation of FAK, STAT3 and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In patient-derived xenograft models the combination significantly reduced tumour growth, with superior efficacy in chromosome 8 gain MPNST.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

MPNST remains the most feared complication in the follow-up of NF1 patients, so any combination strategy deserves attention, particularly as chromosome 8 gain dependency provides a straightforward molecular selection criterion. It must be stressed, however, that the demonstration is entirely preclinical — CRISPR screen, cell lines and patient-derived xenografts — with no human tolerability or efficacy data: nothing to announce in the cancer genetics clinic today. The practical questions ahead are the cumulative toxicity of dual FAK plus RAF/MEK inhibition and whether chromosome 8 status can be documented on routine specimens.

Analysis by Dr Thibaut Benquey