Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors

BRaf^V600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid Cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRaf^V600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRaf^V600E-driven thyroid Cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid Cancer cells to BRaf Inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRaf Inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid Cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid Cancer cells to BRaf Inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.

BRAF mutations; Feedback activation; NG2; Receptor tyrosine kinase (RTK); Thyroid cancer.