Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• ERBB3/HER3 signaling is upregulated in BRAF-mutant melanoma as a survival mechanism against RAF inhibitors.
• This compensatory ERBB3 signaling can limit the effectiveness of current BRAF-targeted therapies.

Purpose of the Study:

• To investigate if cotargeting ERBB3 can enhance the efficacy of RAF inhibitors in melanoma.
• To evaluate the preclinical effectiveness of combining a RAF inhibitor with an ERBB3-blocking antibody.

Main Methods:

• Utilized the ERBB3 function-blocking monoclonal antibody huHER3-8.
• Assessed the inhibition of neuregulin-1 activation and downstream signaling in RAF-inhibited melanoma cells.
• Evaluated the effects of combined BRAF and ERBB3 targeting on cell proliferation, cell death (in vitro), and tumor burden (in vivo).

Main Results:

• The combination therapy decreased melanoma cell proliferation and increased cell death in vitro.
• Combined targeting of BRAF and ERBB3 led to reduced tumor burden in vivo compared to single-agent treatments.
• The addition of huHER3-8 to the RAF inhibitor PLX4720 increased the likelihood of a durable tumor response.

Conclusions:

• This study provides preclinical evidence that blocking ERBB3 signaling can overcome resistance to RAF inhibitors in melanoma.
• Combining ERBB3-neutralizing antibodies with RAF inhibitors offers a potential strategy to improve treatment efficacy and delay tumor regrowth.
• The findings suggest broader implications for targeting ERBB3 in other cancers treated with kinase inhibitors.