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Ref Type | Journal Article | ||||||||||||
PMID | (38728872) | ||||||||||||
Authors | Chen Y, Sang Y, Li S, Xue J, Chen M, Hong S, Lv W, Sehgal K, Xiao H, Liu R | ||||||||||||
Title | The ERK inhibitor GDC-0994 selectively inhibits growth of BRAF mutant cancer cells. | ||||||||||||
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Abstract Text | BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment. |
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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 | melanoma | sensitive | Ravoxertinib + Vemurafenib | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with the combination of Ravoxertinib (GDC-0994) and Zelboraf (vemurafenib) resulted in additive effects, with decreased growth of a melanoma cell line harboring BRAF V600E in culture (PMID: 38728872). | 38728872 |
NRAS Q61K | thyroid gland anaplastic carcinoma | sensitive | Ravoxertinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ravoxertinib (GDC-0994) inhibited viability of an anaplastic thyroid carcinoma cell line harboring NRAS Q61K in culture (PMID: 38728872). | 38728872 |
BRAF V600E | thyroid gland anaplastic carcinoma | sensitive | Ravoxertinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Ravoxertinib (GDC-0994) inhibited viability and colony formation and induced cell cycle arrest in an anaplastic thyroid carcinoma cell line harboring BRAF V600E in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 38728872). | 38728872 |
BRAF V600E | thyroid gland papillary carcinoma | sensitive | Ravoxertinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ravoxertinib (GDC-0994) inhibited viability and colony formation in papillary thyroid carcinoma cell lines harboring BRAF V600E in culture (PMID: 38728872). | 38728872 |
BRAF V600E | melanoma | sensitive | Ravoxertinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ravoxertinib (GDC-0994) inhibited viability and colony formation in melanoma cell lines harboring BRAF V600E in culture (PMID: 38728872). | 38728872 |