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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.
Journal Vol Issue Date Pages Journal Short Title
Translational oncology 45 2024 May 09 101991 Transl Oncol
URL
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 Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
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 anaplastic thyroid 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 papillary thyroid 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 anaplastic thyroid 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