Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus

Area of Science:

• Oncology
• Genomics
• Pharmacogenomics

Background:

• Everolimus, an mTOR inhibitor, shows modest efficacy across various cancers.
• Predictive biomarkers are needed to optimize everolimus treatment.
• Genomic alterations underlying sensitivity to everolimus require investigation.

Purpose of the Study:

• To explore genomic alterations associated with extreme sensitivity to everolimus.
• To identify predictive biomarkers for everolimus therapy.

Main Methods:

• Targeted ultra-deep sequencing of 409 genes in 39 patients with diverse tumor types.
• Analysis of formalin-fixed paraffin-embedded tumor/normal pairs.
• Correlation of genomic alterations with clinical benefit from everolimus.

Main Results:

• Genomic alterations activating the mTOR signaling pathway were found in 45% of patients with clinical benefit.
• Mutations in MTOR, TSC1, TSC2, NF1, PIK3CA, and PIK3CG were associated with everolimus sensitivity.
• Mutations in chromatin remodeling (BAP1) and receptor tyrosine kinase signaling (FGFR4) genes were observed in patients without clinical benefit.

Conclusions:

• mTOR pathway-activating mutations predict sensitivity to everolimus, irrespective of cancer type.
• Targeted sequencing of mTOR pathway genes can identify patients suitable for mTOR inhibitors.