The ERK inhibitor GDC-0994 selectively inhibits growth of BRAF mutant cancer cells

• Published in: Translational oncology Vol. 45; p. 101991
• Main Authors: Chen, Yulu, Sang, Ye, Li, Shiyong, Xue, Junyu, Chen, Mengke, Hong, Shubin, Lv, Weiming, Sehgal, Kartik, Xiao, Haipeng, Liu, Rengyun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2024; Neoplasia Press; Elsevier
• Subjects: BRAF mutation; Cell cycle; ERK inhibitor; Original Research; Targeted therapy; ERK inhibitor; Targeted therapy; Cell cycle; BRAF mutation
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2024.101991

•GDC-0994 inhibits the growth of BRAF mutant cancer cells in vitro and in vivo.•GDC-0994 induces cell cycle arrest in BRAF mutation positive cancer cells.•GDC-0994 treatment affects the expressions of cell cycle-related genes.•BRAF mutation confers sensitivity to multiple ERK1/2 inhibitors. 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.