研究者らが耐性脳腫瘍の有望な治療標的を明らかにした(Researchers reveal promising treatment target for resistant brain cancer)

2024-05-25

2024-05-17 バージニア工科大学(VirginiaTech)

致命的な脳腫瘍である膠芽腫(グリオブラストーマ)の患者にとって、化学療法抵抗性は大きな問題です。現在の標準治療である手術、放射線療法、テモゾロミドを使用した化学療法は効果が限定的であり、腫瘍細胞は迅速に抵抗性を獲得します。
◆バージニア工科大学の研究者は、テモゾロミド治療中の腫瘍細胞生存に重要なPI3K-βシグナル伝達経路を特定し、この経路を阻害することで腫瘍細胞がテモゾロミドに対して感受性を高めることを発見しました。研究結果はiScience誌に掲載され、将来的には血液脳関門を克服するための研究が進められる予定です。

<関連情報>

ホスファチジルイノシトール3キナーゼβによる膠芽腫の化学感受性の選択的制御 Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta

Kevin J. Pridham,Kasen R. Hutchings,Patrick Beck,…,Allison Tegge,Deborah F. Kelly,Zhi Sheng
iScience Published:May 06, 2024
DOI:https://doi.org/10.1016/j.isci.2024.109921

Highlights

•Divergent roles of PI3K kinases in glioblastoma’s chemoresistance

•PI3Kβ outcompetes PI3Kα/δ/γ in chemoresistance

•PI3Kβ inhibitors are effective chemosensitizers

•PI3Kβ regulates drug sensitivity in glioblastoma stem cells

Summary

Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3Kα/β/δ/γ has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma’s chemosensitivity. Here, we report that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kβ being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kβ, defined as MGMT-deficient/PI3Kβ-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kβ-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kβ, but not other kinases, sensitized MGMT-deficient/PI3Kβ-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kβ-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kβ in chemoresistance, making PI3Kβ-selective blockade an effective chemosensitizer for glioblastoma.