Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The RET proto-oncogene, a receptor-tyrosine kinase, is implicated in oncogenesis through activating rearrangements and mutations.
• RET alterations are identified drivers in various solid tumors, including lung and thyroid cancers.
• Current multikinase inhibitors targeting RET have shown modest clinical responses.

Purpose of the Study:

• To review the clinical efficacy of RET-targeted therapies.
• To discuss the challenges and future directions in targeting RET-driven cancers.
• To highlight the need for novel therapeutic strategies for RET-dependent tumors.

Main Methods:

• Review of emerging data on RET-targeted therapies.
• Analysis of clinical response rates to multikinase inhibitors.
• Discussion of the tractability of RET as a drug target.

Main Results:

• RET rearrangements and mutations are actionable oncogenic drivers.
• Limited success of current multikinase inhibitors compared to other targeted therapies.
• No RET-directed targeted therapy has received regulatory approval for specific patient populations.

Conclusions:

• The modest efficacy of current RET inhibitors may stem from a lack of highly specific agents and the inherent challenges of targeting RET.
• Novel therapeutic strategies are essential to enhance clinical outcomes in RET-dependent cancers.
• Improved efficacy is crucial for accelerating regulatory approvals of RET-directed therapies.