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Ref Type Journal Article
PMID (32737157)
Authors Chen C, Zhu S, Zhang X, Zhou T, Gu J, Xu Y, Wan Q, Qi X, Chai Y, Liu X, Chen L, Yan J, Hua Y, Lin F
Title Targeting the Synthetic Vulnerability of PTEN-Deficient Glioblastoma Cells with MCL1 Inhibitors.
URL
Abstract Text 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.

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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
PTEN loss glioblastoma predicted - sensitive GDC-0152 Preclinical - Cell culture Actionable In a preclinical study, GDC-0152 treatment inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma predicted - sensitive Birinapant Preclinical - Cell culture Actionable In a preclinical study, TL32711 (birinapant) treatment inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma sensitive AZD5991 Preclinical - Cell culture Actionable In a preclinical study, AZD5991 treatment inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma sensitive Temozolomide + UMI-77 Preclinical - Cell culture Actionable In a preclinical study, UMI-77 in combination with Temodar (temozolomide) enhanced cytotoxicity and apoptosis, and synergistically inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma sensitive AZD5991 + Temozolomide Preclinical - Cell culture Actionable In a preclinical study, AZD5991 in combination with Temodar (temozolomide) synergistically inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma sensitive S63845 Preclinical - Cell culture Actionable In a preclinical study, S63845 treatment reduced Akt phosphorylation and inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma sensitive A-1210477 Preclinical - Cell culture Actionable In a preclinical study, A-1210477 treatment reduced Akt phosphorylation and inhibited proliferation of PTEN-deficient glioblastoma cells in culture (PMID: 32737157). 32737157
PTEN loss glioblastoma sensitive UMI-77 Preclinical - Cell culture Actionable In a preclinical study, UMI-77 treatment led to enhanced apoptosis, reduced Akt phosphorylation, and inhibited proliferation, colony formation, spheroid formation, and neurosphere formation in PTEN-deficient glioblastoma cell lines in culture (PMID: 32737157). 32737157