Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

By G. Bollag, P. Hirth, J. Tsai, Jiazhong Zhang, P. Ibrahim, Hanna Cho, W. Spevak, Chao Zhang, Ying Zhang, G. Habets and 30 more. Nature, 2010

1,767 citations recorded by the source corpus.

B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

Subfields: Molecular Biology, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/37fda9a29d0b7c4f305557c28fd1350d157bb603

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Citations in the corpus

Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF (2013, neutral): “In addition, BRAF mutant melanomas have an order of magnitude increased uptake of glucose compared to normal tissues in vivo as assessed by functional imaging (Bollag et al., 2010).”
Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. (2012, background): “The ability to direct targeted cancer agents based on tumorspecific molecular abnormalities has had a clear and positive impact on the management of patients with non-small cell lung, breast, colon, skin, and gastrointestinal tumors [3–7].”
Fibroblast heterogeneity in the cancer wound (2014, background): “BRAF mutant melanomas are highly dependent on constitutive BRAF kinase activity, and inhibition of BRAF improves survival in patients (Bollag et al., 2010; Flaherty et al., 2010; Chapman et al., 2011; Sosman et al., 2012).”
RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy (2018, background): “(B) NGL view of the interaction of B-Raf Kinase bound to the US FDA approved anti-neoplastic drug Vemurafenib (PDB ID: 3og7 (55)).”
Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9 (2016, neutral): “1, 2 ) 6,16,17 .”
Melanoma whole exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance (2012, background): “, and the ATP-competitive type I RAF inhibitors, PLX4032 / vemurafenib and GSK2118436 , display remarkable anti-tumour activity leading to overall survival advantage in patients with V600 B-RAF mutant melanoma”
The MAPK pathway across different malignancies: A new perspective (2014, methodology): “Patients with advanced-stage, V600EBRAF-mutated, metastatic melanoma receiving vemurafenib treatment who achieved>80% inhibition of cytoplasmic ERK phosphorylation, as observed in paired pretreatment and on-treatment biopsy samples, demonstrated clinical evidence of partial remission.(52) Recently, ”
Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain (2013, background): “27; 124–133 ORGINAL ARTICLE tumor regression, resulting in improved progression-free and overall survival in patients with metastatic disease (Bollag et al., 2010, 2012).”