Mechanisms of resistance to RET-directed therapies

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The RET proto-oncogene is linked to multiple endocrine neoplasia type 2 and various cancers, including thyroid and lung cancer.
• Specific RET variants are associated with distinct cancer phenotypes, occurring in germline or somatic DNA.
• Somatic RET fusions are implicated in diverse malignancies such as papillary thyroid cancer, non-small-cell lung cancer, and pancreatic cancer.

Purpose of the Study:

• To review the mechanisms of primary and acquired drug resistance to RET inhibitors.
• To highlight the importance of understanding resistance pathways for developing novel therapeutic strategies.
• To identify unmet clinical needs in managing RET-altered cancers.

Main Methods:

• Literature review of studies on RET alterations, cancer phenotypes, and therapeutic resistance.
• Analysis of genomic alterations leading to on-target and bypass resistance.
• Synthesis of findings across multiple cancer types with RET alterations.

Main Results:

• Highly selective RET inhibitors have shown efficacy but are associated with primary and acquired drug resistance.
• Resistance mechanisms include on-target alterations within RET and bypass of RET signaling via alternate oncogenic pathways.
• These resistance mechanisms are conserved across various RET-altered cancers, suggesting common evolutionary trajectories.

Conclusions:

• Understanding RET-mediated drug resistance is critical for advancing cancer therapy.
• Targeting bypass oncogenes offers some therapeutic success, but overcoming on-target RET resistance remains a significant clinical challenge.
• Further research is urgently needed to develop effective strategies against both on-target and bypass resistance mechanisms in RET-altered cancers.