Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Anaplastic thyroid carcinoma (ATC) often exhibits resistance to single-agent targeted therapies due to pathway plasticity.
• Tumor growth can be driven by parallel signaling pathways, necessitating multi-pathway blockade for effective treatment.

Purpose of the Study:

• To investigate the efficacy of combined RAF/MEK and mTOR/PI3K pathway inhibition in a patient with anaplastic thyroid carcinoma (ATC).
• To identify distinct molecular subgroups within ATC based on genetic alterations and transcriptional profiles.
• To explore the co-occurrence of MAPK and PI3K pathway alterations in ATC.

Main Methods:

• Multi-region whole-exome sequencing of diagnostic and autopsy tumor biopsies.
• Meta-analysis of existing DNA and RNA sequencing studies in ATC.
• Analysis of BRAF and PIK3CA mutations and their impact on signaling pathways.

Main Results:

• The patient's ATC harbored both BRAF and PIK3CA mutations, activating MAPK and PI3K/AKT pathways.
• Meta-analysis revealed a 10.3% co-occurrence of MAPK and PI3K pathway alterations in ATC.
• Tumors with these co-occurring mutations exhibited a unique transcriptional profile, suggesting a novel ATC subgroup.

Conclusions:

• BRAF and PIK3CA mutations identify a distinct molecular subset of ATC.
• Simultaneous blockade of MAPK and PI3K pathways is essential for tumor response in this ATC subset.
• The observed synergistic activity between targeted agents can inform future clinical trial designs for ATC.