American Association for Cancer Research
15357163mct200099-sup-237160_2_supp_6400668_qcv88w.pdf (1.81 MB)

Supplementary Figures 1-4 from Targeting the Synthetic Vulnerability of PTEN-Deficient Glioblastoma Cells with MCL1 Inhibitors

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journal contribution
posted on 2023-04-03, 18:23 authored by Chao Chen, Sichao Zhu, Xia Zhang, Tingting Zhou, Jing Gu, Yurong Xu, Quan Wan, Xiao Qi, Yezi Chai, Xiaorong Liu, Lukui Chen, Jie Yan, Yunfen Hua, Fan Lin

Supplemental Figure 1. Kaplan-Meier survival curves of glioma patients with positive or negative MCL1 expression (P-value by log-rank test). Supplemental Figure 2. Layout of apoptotic antibody array and results analysis. Supplemental Figure 3. Evaluation of the anti�GBM effect of the combined treatment of UMI�77 and temozolomide (U+T). Supplemental Figure 4. Combination treatment of temozolomide and UMI-77 in established GBM cell lines.


National Natural Science Foundation of China



PTEN deletion or mutation occurs in 30% to 60% of patients with glioblastoma (GBM) and is associated with poor prognosis. Efficacious therapy for this subgroup of patients is currently lacking. To identify potential target(s) to selectively suppress PTEN-deficient GBM growth, we performed a three-step synthetic lethal screen on LN18 PTEN wild-type (WT) and knockout (KO) isogeneic GBM cell lines using a library containing 606 target-selective inhibitors. A MCL1 inhibitor UMI-77 identified in the screen exhibited excellent suppression on the proliferation, colony formation, 3D spheroid, and neurosphere formation of PTEN-deficient GBM cells. Mechanistically, loss of PTEN in GBM cells led to upregulation of MCL1 in posttranslational level via inhibition of GSK3β, and consequently confer cells resistance to apoptosis. Pharmacologic inhibition or knockdown of MCL1 blocked this PI3K–GSK3β–MCL1 axis and caused reduction of several antiapoptotic proteins, finally induced massive caspase-3 cleavage and apoptosis. In both subcutaneous and orthotopic GBM models, knockdown of MCL1 significantly impaired the in vivo growth of PTEN-deficient xenografts. Moreover, the combination of UMI-77 and temozolomide synergistically killed PTEN-deficient GBM cells. Collectively, our work identified MCL1 as a promising target for PTEN-deficient GBM. For future clinical investigations, priority should be given to the development of a selective MCL1 inhibitor with efficient brain delivery and minimal in vivo toxicity.