Reference Detail

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 + 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