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Ref Type Journal Article
PMID (26466569)
Authors Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, Tsang G, Marimuthu A, Cho H, Wu G, Wang W, Fong D, Nguyen H, Shi S, Womack P, Nespi M, Shellooe R, Carias H, Powell B, Light E, Sanftner L, Walters J, Tsai J, West BL, Visor G, Rezaei H, Lin PS, Nolop K, Ibrahim PN, Hirth P, Bollag G
Title RAF inhibitors that evade paradoxical MAPK pathway activation.
Abstract Text Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.


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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
PLX7904 PLX7904 9 0
PLX8394 PLX8394 25 3
Drug Name Trade Name Synonyms Drug Classes Drug Description
PLX7904 BRAF Inhibitor 25 PLX7904 is a small molecule inhibitor that preferentially inhibits BRAF V600E over wild-type BRAF and CRAF without activating MAPK signaling, therefore leads to growth inhibition in tumor cells (PMID: 26466569, PMID: 28659148).
PLX8394 PLX 8394|PLX-8394|FORE8394|FORE-8394|FORE 8394 BRAF Inhibitor 25 CRAF Inhibitor 12 PLX8394 is a RAF inhibitor that inhibits wild-type and mutant BRAF, as well as CRAF, and does not paradoxically activate MAPK signaling, potentially resulting in decreased proliferation of BRAF-mutant tumor cells (PMID: 26466569, PMID: 24283590, PMID: 28659148, PMID: 30559419).
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
HRAS Q61L skin squamous cell carcinoma no benefit PLX7904 Preclinical - Cell line xenograft Actionable In a preclinical study, PLX7904 did not stimulate growth of Zelboraf (vemurafenib)-induced cutaneous squamous cell carcinoma cells harboring HRAS Q61L in culture or in cell line xenograft models (PMID: 26466569). 26466569
BRAF V600E melanoma sensitive PLX7904 Preclinical - Cell culture Actionable In a preclinical study, PLX7904 inhibited survival of melanoma cell lines harboring monomeric BRAF V600E as well as cells harboring the Zelboraf (vemurafenib)-resistant dimeric BRAF V600E in culture (PMID: 26466569). 26466569
BRAF V600E colorectal cancer sensitive PLX7904 Preclinical - Cell line xenograft Actionable In a preclinical study, PLX7904 inhibited survival of colorectal cancer cells harboring BRAF V600E in culture and demonstrated anti-tumor activity in cell line xenograft models (PMID: 26466569). 26466569