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

ABSTRACT: 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.

SUBMITTER: Sen S 

PROVIDER: S-EPMC7476413 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Dual inhibition of BRAF and mTOR in <i>BRAF</i><sup><i>V600E</i></sup> -mutant pediatric, adolescent, and young adult brain tumors.

Sen Shiraj S   Tanaka Ryuma R   Khatua Soumen S   Zaky Wafik W   Janku Filip F   Penas-Prado Marta M   Weathers Shiao-Pei SP   Behrang Amini A   Roszik Jason J   Subbiah Vivek V  

Cold Spring Harbor molecular case studies 20200825 4

Although BRAF inhibition has demonstrated activity in <i>BRAF</i><sup><i>V600</i></sup> -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 p  ...[more]

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