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Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

ABSTRACT: Background:RAS effector signaling pathways such as PI3K/mTOR and ERK are frequently dysregulated in glioblastoma. While small molecule targeted therapies against these pathways have appeared promising in preclinical studies, they have been disappointing in clinical trials due to toxicity and de novo and adaptive resistance. To identify predictors of glioblastoma sensitivity to dual pathway inhibition with mTORC1/2 and MEK inhibitors, we tested these agents, alone and in combination, in a cohort of genomically characterized glioblastoma cell lines. Methods:Seven genomically characterized, patient-derived glioblastoma neurosphere cell lines were evaluated for their sensitivity to the dual mTORC1/2 kinase inhibitor sapanisertib (MLN0128, TAK-228) alone or in combination with the MEK1/2 inhibitor trametinib (GSK1120212), using assessment of proliferation and evaluation of the downstream signaling consequences of these inhibitors. Results:Sapanisertib inhibited cell growth in neurosphere lines, but induced apoptosis only in a subset of lines, and did not completely inhibit downstream mTOR signaling via ribosomal protein S6 (RPS6). Growth sensitivity to MEK inhibitor monotherapy was observed in a subset of lines defined by loss of NF1, was predicted by an ERK-dependent expression signature, and was associated with effective phospho-RPS6 inhibition. In these lines, combined MEK/mTOR treatment further inhibited growth and induced apoptosis. Combined MEK and mTOR inhibition also led to modest antiproliferative effects in lines with intact NF1 and insensitivity to MEK inhibitor monotherapy. Conclusions:These data demonstrate that combined MEK/mTOR inhibition is synergistic in glioblastoma cell lines and may be more potent in NF1-deficient glioblastoma.

SUBMITTER: Schreck KC

PROVIDER: S-EPMC7668446 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

Schreck Karisa C KC Allen Amy N AN Wang Jiawan J Pratilas Christine A CA

Neuro-oncology advances 20200101 1

<h4>Background</h4>RAS effector signaling pathways such as PI3K/mTOR and ERK are frequently dysregulated in glioblastoma. While small molecule targeted therapies against these pathways have appeared promising in preclinical studies, they have been disappointing in clinical trials due to toxicity and de novo and adaptive resistance. To identify predictors of glioblastoma sensitivity to dual pathway inhibition with mTORC1/2 and MEK inhibitors, we tested these agents, alone and in combination, in a ...[more]

PMID: 33235998

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Project description:Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients with BRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

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Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

Publications

Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

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