Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors

Although BRAF inhibition has demonstrated activity in BRAF(V600)–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary a...

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Detalles Bibliográficos
Autores principales: Sen, Shiraj, Tanaka, Ryuma, Khatua, Soumen, Zaky, Wafik, Janku, Filip, Penas-Prado, Marta, Weathers, Shiao-Pei, Behrang, Amini, Roszik, Jason, Subbiah, Vivek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Research Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476413/
https://www.ncbi.nlm.nih.gov/pubmed/32843426
http://dx.doi.org/10.1101/mcs.a005041
Descripción
Sumario:Although BRAF inhibition has demonstrated activity in BRAF(V600)–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF(V600)-mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.

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