Mechanisms of Adaptive Resistance to Targeted Therapy in RET-Aberrant Cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Targeted therapies are crucial for oncogene-driven cancers but are often limited by acquired resistance.
• Treatment resistance leads to disease progression and poorer patient outcomes.
• Understanding resistance mechanisms is key to developing more effective cancer treatments.

Purpose of the Study:

• To investigate the mechanisms of adaptive resistance to RET-targeted therapies in RET-altered cancers.
• To identify potential therapeutic vulnerabilities that can overcome treatment resistance.
• To explore the role of YAP-dependent human epidermal growth factor receptor 3 (HER3) activation in resistance.

Main Methods:

• Analysis of patient-derived models and cell lines with RET alterations.
• Investigating the signaling pathways involved in adaptive resistance.
• Utilizing pharmacological inhibitors to target identified vulnerabilities.

Main Results:

• YAP-dependent activation of human epidermal growth factor receptor 3 (HER3) was identified as a key mechanism of adaptive resistance.
• This HER3 activation confers resistance to existing RET inhibitors.
• Targeting this HER3 vulnerability showed promise in restoring sensitivity to RET-targeted therapies.

Conclusions:

• YAP-dependent HER3 activation represents a significant therapeutic vulnerability in RET-altered cancers.
• Combining RET inhibitors with strategies targeting HER3 activation may overcome adaptive resistance.
• This finding offers a promising new approach to improve treatment responses and patient outcomes in RET-altered cancers.