Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	19	10	2020 Oct	2001-2011	Mol Cancer Ther

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	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
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	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	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	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	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	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	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