VEGF blockade enhances the antitumor effect of BRAFV600E inhibition

Area of Science:

• Oncology
• Cancer Biology
• Molecular Therapy

Background:

• Acquired resistance to targeted therapies like BRAF inhibitors is a significant challenge in cancer treatment.
• BRAF-mutant tumors often develop resistance, limiting long-term disease control.

Purpose of the Study:

• To investigate the efficacy of combined BRAF and VEGF pathway inhibition in overcoming resistance in BRAF-mutant mouse models.
• To explore the underlying mechanisms contributing to the enhanced anti-tumor response.

Main Methods:

• Utilized BRAF-mutant mouse models to assess the effects of single versus combined BRAF and VEGF inhibition.
• Analyzed tumor growth, apoptosis, lung colonization, and the development of acquired resistance.
• Investigated changes in tumor microenvironment, including vascular normalization, hypoxia, extracellular matrix remodeling, macrophage phenotype, and cancer-associated fibroblasts.
• Performed molecular analyses to identify transcriptional signatures associated with the therapeutic response.

Main Results:

• Combined BRAF and VEGF inhibition induced significant apoptosis and long-lasting tumor suppression.
• This combination reduced lung metastasis and delayed the onset of acquired resistance to BRAF inhibitors.
• Therapeutic effects were associated with tumor vascular normalization, reduced hypoxia, extracellular matrix remodeling, M1-like macrophage infiltration, and decreased cancer-associated fibroblasts.
• A novel transcriptional signature was identified, correlating with sustained anti-tumor efficacy.

Conclusions:

• Combination therapy targeting both BRAF and VEGF pathways offers a promising strategy to overcome resistance in BRAF-mutant cancers.
• The observed efficacy is supported by modulation of the tumor microenvironment and molecular reprogramming.
• These findings provide a strong biological rationale for combining BRAF inhibitors with anti-angiogenic agents in clinical settings to manage resistance.