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Ref Type Journal Article
PMID (26504226)
Authors Costa HA, Leitner MG, Sos ML, Mavrantoni A, Rychkova A, Johnson JR, Newton BW, Yee MC, De La Vega FM, Ford JM, Krogan NJ, Shokat KM, Oliver D, Halaszovich CR, Bustamante CD
Title Discovery and functional characterization of a neomorphic PTEN mutation.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 112
Issue 45
Date 2015 Nov 10
URL
Abstract Text Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient 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
PTEN A126G missense loss of function PTEN A126G lies within the tensin-type phosphatase domain of the Pten protein (UniProt.org). A126G confers a loss of function to the Pten protein as demonstrated by a shift in substrate specificity of Pten from 3- to 5-phosphatase (PMID: 29987362), an inability to regulate Pi3k/Akt signaling, and increased cell proliferation and transformation in culture (PMID: 26504226).
PTEN A126P missense loss of function PTEN A126P lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). A126P demonstrates loss of phosphatase activity (PMID: 26504226) and reduced Pten protein stability, and fails to suppress Akt phosphorylation in cell culture, and delays developmental growth in flies (PMID: 32350270).
PTEN A126S missense loss of function PTEN A126S lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). A126S results in a loss of Pten phosphatase activity in culture and reduced inhibition of Pi3k activity in yeast (PMID: 26504226, PMID: 21828076).
PTEN A126V missense loss of function PTEN A126V lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). A126V results in a loss of Pten phosphatase activity in cell culture and loss of Pi3k inhibition in yeast (PMID: 21828076, PMID: 26504226).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN A126G prostate cancer sensitive AZD6482 Preclinical Actionable In a preclinical study, AZD6482 inhibited Akt signaling and cell migration in prostate cancer cell lines overexpressing PTEN A126G (PMID: 26504226). 26504226
PTEN A126G prostate cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Alpelisib (BYL719) inhibited Akt signaling and cell migration in prostate cancer cells expressing PTEN A126G in culture (PMID: 26504226). 26504226