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

@article{Bollag2010ClinicalEO,
  title={Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma},
  author={Gideon Bollag and Peter Hirth and James H. Tsai and Jiazhong Zhang and Prabha N. Ibrahim and Hanna Cho and Wayne R Spevak and Chao Zhang and Ying Zhang and Gaston G. M. Habets and Elizabeth A. Burton and Bernice Huimin Wong and Garson Tsang and Brian L. West and Ben J. Powell and Rafe Shellooe and Adhirai Marimuthu and Hoa T. Nguyen and Kam Y. J. Zhang and Dean R. Artis and Joseph Schlessinger and Fei Su and Brian Higgins and Raman Mahadevan Iyer and Kurt D’Andrea and Astrid Koehler and Michael Stumm and Paul S. Lin and Richard J Lee and Joseph F. Grippo and Igor Puzanov and Kevin B. Kim and Antoni Ribas and Grant A. McArthur and Jeffrey A. Sosman and Paul B. Chapman and Keith T. Flaherty and Xiaowei Xu and Katherine L. Nathanson and Keith B. Nolop},
  journal={Nature},
  year={2010},
  volume={467},
  pages={596 - 599}
}
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… 
Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma.
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Within the clinical dose range, there is a RAF inhibitor dose that is an inflection point for the toxicity and efficacy of this regimen, and within this patient, the effect on toxicities of different dose levels of these agents is characterized.
Development of small-molecule therapeutics and strategies for targeting RAF kinase in BRAF-mutant colorectal cancer
TLDR
The existing mechanism of RAF kinases in CRC, including MAPK feedback reactivation of resistance to RAF inhibitors, is summarized and the development of three generations of RAF inhibitors and different therapeutic strategies including the combination of EGFR, BRAF, and PI3K inhibitors for BRAFm CRC treatment is summarized.
Parallel and Serial Blockade Strategies in BRAF-Mutant Melanoma
TLDR
Initial preclinical and clinical studies support that resistance mechanisms may broadly be characterized as those that result in re-activation of the RAS-RAF-MEK-ERK signaling pathway, or (2) activation of other pro-survival mediators.
The “SWOT” of BRAF Inhibition in Melanoma: RAF Inhibitors, MEK Inhibitors or Both?
TLDR
The strengths, weaknesses, opportunities and threats of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies are discussed.
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