Challenges and strategies to combat resistance mechanisms in thyroid cancer therapeutics.

BACKGROUND: BRAF V600E and K/N/H RAS mutations and oncogenic kinase fusions involving NTRK, RET, ALK and ROS1 have been identified as actionable targets in thyroid cancer. These driver alterations lead to onocogene addiction which has been successfully exploited through tyrosine kinase inhibitors. Acquired resistance may develop following an initial response requiring a therapeutic pivot to new therapies.

SUMMARY: Several pathways for development of acquired resistance have been identified. These encompass acquired on-target gene mutation impeding drug activity and upregulation of bypass kinase signaling pathways leading to tumour progression. Biopsy of resistant lesions (liquid or tissue) and subsequent molecular analysis can assist with new therapeutic strategies.

CONCLUSIONS: Progression-free survival is curtailed by developing acquired resistance. To minimise this therapeutic liability, clinicians must be anticipatory in identifying the drivers and characterising mechanisms of on target resistance.