Reference Detail

Ref Type

Journal Article

PMID

(38714355)

Authors

Ioannou M, Lalwani K, Ayanlaja AA, Chinnasamy V, Pratilas CA, Schreck KC

Title

MEK Inhibition Enhances the Antitumor Effect of Radiotherapy in NF1-Deficient Glioblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	23	9	2024 Sep 04	1261-1272	Mol Cancer Ther

URL

Abstract Text

Individuals with neurofibromatosis type 1, an autosomal dominant neurogenetic and tumor predisposition syndrome, are susceptible to developing low-grade glioma and less commonly high-grade glioma. These gliomas exhibit loss of the neurofibromin gene [neurofibromin type 1 (NF1)], and 10% to 15% of sporadic high-grade gliomas have somatic NF1 alterations. Loss of NF1 leads to hyperactive RAS signaling, creating opportunity given the established efficacy of MEK inhibitors in plexiform neurofibromas and some individuals with low-grade glioma. We observed that NF1-deficient glioblastoma neurospheres were sensitive to the combination of an MEK inhibitor (mirdametinib) with irradiation, as evidenced by synergistic inhibition of cell growth, colony formation, and increased cell death. In contrast, NF1-intact neurospheres were not sensitive to the combination, despite complete ERK pathway inhibition. No neurosphere lines exhibited enhanced sensitivity to temozolomide combined with mirdametinib. Mirdametinib decreased transcription of homologous recombination genes and RAD51 foci, associated with DNA damage repair, in sensitive models. Heterotopic xenograft models displayed synergistic growth inhibition to mirdametinib combined with irradiation in NF1-deficient glioma xenografts but not in those with intact NF1. In sensitive models, benefits were observed at least 3 weeks beyond the completion of treatment, including sustained phosphor-ERK inhibition on immunoblot and decreased Ki-67 expression. These observations demonstrate synergistic activity between mirdametinib and irradiation in NF1-deficient glioma models and may have clinical implications for patients with gliomas that harbor germline or somatic NF1 alterations.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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
BRAF V600E	glioblastoma	sensitive	PD-0325901 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of PD-0325901 and radiotherapy synergistically inhibited cell growth of glioblastoma cell lines harboring BRAF V600E in culture (PMID: 38714355).	38714355
BRAF V600E	glioblastoma	conflicting	PD-0325901	Preclinical - Cell culture	Actionable	In a preclinical study, PD-0325901 inhibited growth of glioblastoma cell lines harboring BRAF V600E in culture (PMID: 38714355).	38714355