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Ref Type Journal Article
PMID (23674493)
Authors Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J
Title PI3K pathway dependencies in endometrioid endometrial cancer cell lines.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 19
Issue 13
Date 2013 Jul 01
URL
Abstract Text Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110β signaling for survival.Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110α, and p110β isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells.EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110β inhibitors GSK2636771 and AZD6482, and only in combination with the p110α selective inhibitor A66 was a decrease in cell viability observed.Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110β alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required.

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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
AZD6482 AZD6482 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD6482 KIN-193|AZD-6482 PIK3CB inhibitor 8 PIK3CD inhibitor 25 AZD6482 inhibits PIK3CB and PIK3CD, preventing the activation of the PI3K signaling pathway and inhibiting tumor cell proliferation, motility, and survival (PMID: 24992874, PMID: 23674493, PMID: 31292159, PMID: 30542720).
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
PIK3CA mutant endometrial cancer sensitive Pictilisib Preclinical Actionable In a preclinical study, endometrioid endometrial cancer cell lines harboring PIK3CA mutations demonstrated increased sensitivity to GDC-0941 (Pictilisib) induced growth inhibition comparing to PIK3CA wild-type cells in culture (PMID: 23674493). 23674493