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Targeting oncogenic Raf protein-serine/threonine kinases in human cancers.
Pharmacol Res. 2018 09; 135:239-258.PR

Abstract

The Ras-Raf-MEK-ERK signal transduction cascade is arguably the most important oncogenic pathway in human cancers. Ras-GTP promotes the formation of active homodimers or heterodimers of A-Raf, B-Raf, and C-Raf by an intricate process. These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2. The latter catalyze the regulatory phosphorylation of dozens of cytosolic and nuclear proteins. The X-ray crystal structure of B-Raf-MEK1 depicts a face-to-face dimer with interacting activation segments; B-Raf is in an active conformation and MEK1 is in an inactive conformation. Besides the four traditional components in the Ras-Raf-MEK-ERK signaling module, scaffolding proteins such as Kinase Suppressor of Ras (KSR1/2) play an important role in this signaling cascade by functioning as a scaffold protein. RAS mutations occur in about 30% of all human cancers. Moreover, BRAFV600E mutations occur in about 8% of all cancers making this the most prevalent oncogenic protein kinase. Vemurafenib and dabrafenib are B-RafV600E inhibitors that were approved for the treatment of melanomas bearing the V600E mutation. Coupling MEK1/2 inhibitors with B-Raf inhibitors is more effective in treating such melanomas and dual therapy is now the standard of care. Vemurafenib and cobimetanib, dabrafenib and trametinib, and encorafenib plus binimetinib are the FDA-approved combinations for the treatment of BRAFV600E melanomas. Although such mutations occur in other neoplasms including thyroid, colorectal, and non-small cell lung cancers, these agents are not as effective in treating these non-melanoma neoplasms. Vemurafenib and dabrafenib produce the paradoxical activation of the MAP kinase pathway in wild type BRAF cells. The precise mechanism for this activation is unclear, but drug-induced Raf activating side-to-side dimerization appears to be an essential step. Although 63%-76% of all people with advanced melanoma with the BRAF V600E mutation derive clinical benefit from combination therapy, median progression-free survival lasts only about nine months and 90% of patients develop resistance within one year. The various secondary resistance mechanisms include NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAP kinase pathway alterations (11%). Vemurafenib and dabrafenib bind to an inactive form of B-Raf (αC-helixout and DFG-Din) and are classified as type I½ inhibitors. LY3009120 and lifirafenib, which are in the early drug-development stage, bind to a different inactive form of B-Raf (DFG-Dout) and are classified as type II inhibitors. Besides targeting B-Raf and MEK protein kinases, immunotherapies that include ipilimumab, pembrolizumab, and nivolumab have been FDA-approved for the treatment of melanomas. Current clinical trials are underway to determine the optimal usage of targeted and immunotherapies.

Authors+Show Affiliations

Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, North Carolina 28742-8814, United States. Electronic address: rrj@brimr.org.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

30118796

Citation

Roskoski, Robert. "Targeting Oncogenic Raf Protein-serine/threonine Kinases in Human Cancers." Pharmacological Research, vol. 135, 2018, pp. 239-258.
Roskoski R. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res. 2018;135:239-258.
Roskoski, R. (2018). Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacological Research, 135, 239-258. https://doi.org/10.1016/j.phrs.2018.08.013
Roskoski R. Targeting Oncogenic Raf Protein-serine/threonine Kinases in Human Cancers. Pharmacol Res. 2018;135:239-258. PubMed PMID: 30118796.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. A1 - Roskoski,Robert,Jr Y1 - 2018/08/15/ PY - 2018/08/09/received PY - 2018/08/13/accepted PY - 2018/8/18/pubmed PY - 2019/4/11/medline PY - 2018/8/18/entrez KW - (PubMED CID: 11707110) KW - 50922675) KW - Binimetinib (PubMED CID: 10288191) KW - Catalytic spine KW - Cobimetanib (PubMED CID: 16222096) KW - Dabrafenib: (PubMED CID: 44462760) KW - Encorafenib: (PubMED CID KW - K/E/D/D KW - LY3009120 (PubMED CID: 71721540) KW - Lifirafenib: (PubMED CID:89670174) KW - Melanoma KW - PLX7904: (PubMED CID: 901169945) KW - Protein kinase inhibitor classification KW - Protein kinase structure KW - Sorafenib: (PubMED CID: 216239) KW - Targeted cancer therapy KW - Trametinib KW - Vemurafenib: (PubMED CID: 42611257) SP - 239 EP - 258 JF - Pharmacological research JO - Pharmacol. Res. VL - 135 N2 - The Ras-Raf-MEK-ERK signal transduction cascade is arguably the most important oncogenic pathway in human cancers. Ras-GTP promotes the formation of active homodimers or heterodimers of A-Raf, B-Raf, and C-Raf by an intricate process. These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2. The latter catalyze the regulatory phosphorylation of dozens of cytosolic and nuclear proteins. The X-ray crystal structure of B-Raf-MEK1 depicts a face-to-face dimer with interacting activation segments; B-Raf is in an active conformation and MEK1 is in an inactive conformation. Besides the four traditional components in the Ras-Raf-MEK-ERK signaling module, scaffolding proteins such as Kinase Suppressor of Ras (KSR1/2) play an important role in this signaling cascade by functioning as a scaffold protein. RAS mutations occur in about 30% of all human cancers. Moreover, BRAFV600E mutations occur in about 8% of all cancers making this the most prevalent oncogenic protein kinase. Vemurafenib and dabrafenib are B-RafV600E inhibitors that were approved for the treatment of melanomas bearing the V600E mutation. Coupling MEK1/2 inhibitors with B-Raf inhibitors is more effective in treating such melanomas and dual therapy is now the standard of care. Vemurafenib and cobimetanib, dabrafenib and trametinib, and encorafenib plus binimetinib are the FDA-approved combinations for the treatment of BRAFV600E melanomas. Although such mutations occur in other neoplasms including thyroid, colorectal, and non-small cell lung cancers, these agents are not as effective in treating these non-melanoma neoplasms. Vemurafenib and dabrafenib produce the paradoxical activation of the MAP kinase pathway in wild type BRAF cells. The precise mechanism for this activation is unclear, but drug-induced Raf activating side-to-side dimerization appears to be an essential step. Although 63%-76% of all people with advanced melanoma with the BRAF V600E mutation derive clinical benefit from combination therapy, median progression-free survival lasts only about nine months and 90% of patients develop resistance within one year. The various secondary resistance mechanisms include NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAP kinase pathway alterations (11%). Vemurafenib and dabrafenib bind to an inactive form of B-Raf (αC-helixout and DFG-Din) and are classified as type I½ inhibitors. LY3009120 and lifirafenib, which are in the early drug-development stage, bind to a different inactive form of B-Raf (DFG-Dout) and are classified as type II inhibitors. Besides targeting B-Raf and MEK protein kinases, immunotherapies that include ipilimumab, pembrolizumab, and nivolumab have been FDA-approved for the treatment of melanomas. Current clinical trials are underway to determine the optimal usage of targeted and immunotherapies. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/30118796/Targeting_oncogenic_Raf_protein_serine/threonine_kinases_in_human_cancers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(18)31188-5 DB - PRIME DP - Unbound Medicine ER -