Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	112	45	2015 Nov 10	13976-81	Proc Natl Acad Sci U S A

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
PTEN	A126G	missense	loss of function	PTEN A126G lies within the phosphatase tensin-type 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	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
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