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Ref Type | Journal Article | ||||||||||||
PMID | (38795180) | ||||||||||||
Authors | Sui F, Wang G, Liu J, Yuan M, Chen P, Yao Y, Zhang S, Ji M, Hou P | ||||||||||||
Title | Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors. | ||||||||||||
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Abstract Text | BRAFV600E 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 BRAFV600E 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 BRAFV600E-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. |
Molecular Profile | Treatment Approach |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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BRAF V600E | thyroid cancer | sensitive | Lenvatinib + PLX4720 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, treatment with the combination of PLX4720 and Lenvima (lenvatinib) inhibited proliferation of thyroid cancer cell lines harboring BRAF V600E in culture and resulted in greater tumor growth inhibition than PLX4720 alone in a cell line xenograft model (PMID: 38795180). | 38795180 |
BRAF V600E | thyroid cancer | sensitive | PLX4720 + Sorafenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, treatment with the combination of PLX4720 and Nexavar (sorafenib) inhibited proliferation of thyroid cancer cell lines harboring BRAF V600E in culture and resulted in greater tumor growth inhibition than PLX4720 alone in a cell line xenograft model (PMID: 38795180). | 38795180 |