Reference Detail

Ref Type

Journal Article

PMID

(17376864)

Authors

Gymnopoulos M, Elsliger MA, Vogt PK

Title

Rare cancer-specific mutations in PIK3CA show gain of function.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	104	13	2007 Mar 27	5569-74	Proc Natl Acad Sci U S A

URL

Abstract Text

Fifteen rare cancer-derived mutants of PIK3CA, the gene coding for the catalytic subunit p110alpha of phosphatidylinositol 3-kinase (PI3K), were examined for their biological and biochemical properties. Fourteen of these mutants show a gain of function: they induce rapamycin-sensitive oncogenic transformation of chicken embryo fibroblasts, constitutively activate Akt and TOR-mediated signaling, and show enhanced lipid kinase activity. Mapping of these mutants on a partial structural model of p110alpha suggests three groups of mutants, defined by their location in distinct functional domains of the protein. We hypothesize that each of these three groups induces a gain of PI3K function by a different molecular mechanism. Mutants in the C2 domain increase the positive surface charge of this domain and therefore may enhance the recruitment of p110alpha to cellular membranes. Mutants in the helical domain map to a contiguous surface of the protein and may affect the interaction with other protein(s). Mutants in the kinase domain are located near the hinge of the activation loop. They may alter the position and mobility of the activation loop. Arbitrarily introduced mutations that have no detectable phenotype map either to the interior of the protein or are positioned on a surface region that lies opposite to the exposed surfaces containing gain-of-function mutants. Engineered mutants that exchange acidic or neutral residues for basic residues on the critical surfaces show a gain of function.

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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
PIK3CA	C420R	missense	gain of function	PIK3CA C420R lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). C420R confers a gain of function on Pik3ca, as indicated by constitutive phosphorylation of downstream targets Akt and S6, increased cell proliferation and migration, and is transforming in cell culture (PMID: 17376864, PMID: 29533785, PMID: 34779417).
PIK3CA	E116K	missense	no effect	PIK3CA E116K does not lie within any known functional domains of the Pik3ca protein (UniProt.org). E116K phosphorylates Akt to similar level of wild-type Pik3ca and is not transforming in culture (PMID: 17376864).
PIK3CA	E545A	missense	gain of function	PIK3CA E545A is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E545A confers a gain of function on the Pik3ca protein as demonstrated by increased phosphorylation of Akt and transformation in cell culture (PMID: 17376864, PMID: 29533785).
PIK3CA	E545G	missense	gain of function	PIK3CA E545G is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E545G confers a gain of function on the Pik3ca protein as demonstrated by increased phosphorylation of Akt and transformation in cell culture (PMID: 17376864, PMID: 29533785).
PIK3CA	H1047Y	missense	gain of function	PIK3CA H1047Y is a hotspot mutation that lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). H1047Y confers a gain of function on the Pik3ca protein as indicated by increased phosphorylation of Akt, activation of downstream signaling, and is transforming in cell culture (PMID: 17376864, PMID: 29533785).
PIK3CA	K111N	missense	gain of function	PIK3CA K111N lies within the region linking the PI3K-ABD and PI3K-RBD domains of the Pik3ca protein (UniProt.org). K111N results in increased phosphorylation of Akt, activation of downstream signaling, increased cell proliferation and migration, and is transforming in cell culture (PMID: 17376864, PMID: 29533785, PMID: 34779417).
PIK3CA	M1043I	missense	gain of function	PIK3CA M1043I lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). M1043I confers a gain of function on the Pik3ca protein as indicated by in increased phosphorylation of Akt, activation of downstream signaling, and transformation in cell culture (PMID: 17376864, PMID: 29533785).
PIK3CA	M1043V	missense	gain of function	PIK3CA M1043V lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). M1043V results in increased phosphorylation of Akt, activation of downstream signaling, increased cell proliferation and migration, and is transforming in cell culture (PMID: 17376864, PMID: 29533785, PMID: 34779417).
PIK3CA	N345K	missense	gain of function	PIK3CA N345K lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). N345K results in increased phosphorylation of Akt, activation of downstream signaling, increased cell proliferation and migration, and is transforming in cell culture (PMID: 17376864, PMID: 29533785, PMID: 34779417).
PIK3CA	P539R	missense	gain of function	PIK3CA P539R lies within the PIK helical domain of the Pik3ca protein (UniProt.org). P539R increases the stability of the Pik3ca protein, confers a gain of function, as indicated by constitutive phosphorylation of downstream targets Akt and S6, and is transforming in cell culture (PMID: 18951408, PMID: 17376864, PMID: 29533785).
PIK3CA	Q546K	missense	gain of function	PIK3CA Q546K lies within the PIK helical domain of the Pik3ca protein (UniProt.org, PMID: 17376864). Q546K confers a gain of function to Pik3ca as indicated by constitutive phosphorylation of downstream targets Akt and S6, and is transforming in cell culture (PMID: 17376864, PMID: 29533785).
PIK3CA	Q546P	missense	gain of function	PIK3CA Q546P lies within the PIK helical domain of the Pik3ca protein (UniProt.org). Q546P results in increased phosphorylation of Akt, activation of downstream signaling, and is transforming in cell culture (PMID: 17376864, PMID: 29533785).
PIK3CA	T1025S	missense	gain of function	PIK3CA T1025S lies within the PI3K/PI4K domain in the Pik3ca protein (UniProt.org). T1025S confers a gain of function to the Pik3ca protein as indicated by constitutive activation of downstream signaling and transformation in cultured cells (PMID: 17376864).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA C420R	Advanced Solid Tumor	sensitive	Sirolimus	Preclinical	Actionable	In a preclinical study, cells expressing PIK3CA C420R were sensitive to Rapamune (sirolimus) in culture (PMID: 17376864).	17376864
PIK3CA M1043V	Advanced Solid Tumor	sensitive	Sirolimus	Preclinical	Actionable	In a preclinical study, Rapamune (sirolimus) inhibited proliferation in cultured cells expressing PIK3CA M1043V (PMID: 17376864).	17376864