Reference Detail

Ref Type

Journal Article

PMID

(26058079)

Authors

Stratikopoulos EE, Dendy M, Szabolcs M, Khaykin AJ, Lefebvre C, Zhou MM, Parsons R

Title

Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	27	6	2015 Jun 8	837-51	Cancer Cell

URL

Abstract Text

Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy.

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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 mutant	breast cancer	predicted - sensitive	MS417 + Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, Pictilisib (GDC-0941) and MS417 in combination resulted in improved growth inhibition and increased cell death compared to either agent alone in a PTEN-mutant breast cancer cell line in culture (PMID: 26058079).	26058079
PIK3CA mutant	colorectal cancer	predicted - sensitive	MS417 + Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, Pictilisib (GDC-0941) and MS417 in combination resulted in improved growth inhibition and increased cell death compared to either agent alone in colorectal cancer cell lines harboring PIK3CA mutations in culture (PMID: 26058079).	26058079