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Ref Type Journal Article
PMID (26627007)
Authors Dogruluk T, Tsang YH, Espitia M, Chen F, Chen T, Chong Z, Appadurai V, Dogruluk A, Eterovic AK, Bonnen PE, Creighton CJ, Chen K, Mills GB, Scott KL
Title Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 75 24 2015 Dec 15 5341-54 Cancer Res
URL
Abstract Text Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. Although PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07% to 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of mitogen-activated protein kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent.

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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
PIK3CA A1020V missense no effect PIK3CA A1020V lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). A1020V demonstrates transformation potential and supports cell survival to similar level of wild-type Pik3ca protein in cell culture (PMID: 26627007, PMID: 29533785).
PIK3CA E453K missense gain of function PIK3CA E453K lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). E453K results in increased phosphorylation of Akt and Mek1/2, enhanced cell survival, increased cell proliferation and migration, and is transforming in culture (PMID: 26627007, PMID: 29533785, PMID: 34779417).
PIK3CA E542K missense gain of function PIK3CA E542K is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E542K results in increased phosphorylation of Akt, growth factor-independent cell survival, and is transforming in cell culture (PMID: 16533766, PMID: 26627007, PMID: 29533785).
PIK3CA E542V missense gain of function PIK3CA E542V is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E542V confers a gain of function on Pik3ca, as indicated by increased phosphorylation of Akt and Mek1/2, growth-factor independent cell survival, and is transforming in culture (PMID: 26627007, PMID: 29533785).
PIK3CA E545K missense gain of function PIK3CA E545K is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E545K results in increased phosphorylation of Akt and Mek1/2, growth factor-independent cell survival, and is transforming in culture (PMID: 26627007, PMID: 29533785).
PIK3CA E545Q missense gain of function - predicted PIK3CA E545Q is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E545Q results in growth factor-independent cell survival and transformation in culture (PMID: 26627007, PMID: 29533785), and therefore, is predicted to lead to a gain of Pik3ca protein function.
PIK3CA G1049R missense gain of function PIK3CA G1049R lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). G1049R results in increased phosphorylation of Akt and Mek1/2, growth factor-independent cell survival, and transforming in cell culture (PMID: 26627007, PMID: 29533785).
PIK3CA H1047L missense gain of function PIK3CA H1047L is a hotspot mutation that lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). H1047L results in increased phosphorylation of Akt and Mek1/2, growth factor-independent cell survival, and transformation in cell culture (PMID: 26627007, PMID: 29533785).
PIK3CA H1047R missense gain of function PIK3CA H1047R is a hotspot mutation that lies within the kinase domain of the Pik3ca protein (UniProt.org). H1047R results in increased phosphorylation of Akt and Mek1/2, growth factor-independent cell survival, and transformation in cell culture (PMID: 26627007, PMID: 29533785).
PIK3CA H701P missense no effect PIK3CA H701P does not lie within any known functional domains of the Pik3ca protein (UniProt.org). H701P demonstrates transformation potential and ability to promote growth factor-independent cell survival at similar levels to wild-type Pik3ca protein in cell culture (PMID: 26627007, PMID: 29533785).
PIK3CA I31M missense no effect PIK3CA I31M lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). I31M demonstrates transformation potential and ability to promote growth factor-independent cell survival at similar levels to wild-type Pik3ca protein in cell culture (PMID: 26627007, PMID: 29533785 ).
PIK3CA N1044K missense gain of function PIK3CA N1044K lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). N1044K confers a gain of function to Pik3ca protein as indicated by increased cell survival and transforming ability in cell culture (PMID: 26627007, PMID: 29533785).
PIK3CA N345I missense gain of function - predicted PIK3CA N345I lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). N345I results in increased cell survival, but was not transforming in cell culture in one study (PMID: 26627007), but in two other studies, demonstrated increased transformation ability in multiple cell lines compared to wild-type Pik3ca in culture (PMID: 29533785, PMID: 29636477), and therefore, is predicted to lead to a gain of Pik3ca protein function.
PIK3CA Q546E missense gain of function - predicted PIK3CA Q546E lies within the PIK helical domain of the Pik3ca protein (UniProt.org). Q546E results in increased cell survival and transforming ability in culture (PMID: 26627007, PMID: 29533785), and therefore, is predicted to lead to a gain of Pik3ca protein function.
PIK3CA Q546R missense gain of function PIK3CA Q546R lies within the PIK helical domain of the Pik3ca protein (UniProt.org). Q546R results in increased cell proliferation, migration, and Akt phosphorylation (PMID: 34779417) and increased cell survival and transforming ability in culture (PMID: 26627007, PMID: 29533785, PMID: 34779417).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA G1049R breast cancer sensitive Alpelisib Preclinical Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA G1049R breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA Q546K breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA E545K breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA E542K breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E542K in culture (PMID: 26627007). 26627007
PIK3CA H1047R breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007
PIK3CA G1049R breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA N345K breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA H1047L breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047L in culture (PMID: 26627007). 26627007
PIK3CA N345K Advanced Solid Tumor sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA Q546K breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA N345K breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA H1047L breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047L in culture (PMID: 26627007). 26627007
PIK3CA H1047R breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007
PIK3CA Q546K breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA Q546K breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA H1047L breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047L in culture (PMID: 26627007). 26627007
PIK3CA E545K breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA E545K breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA E542K breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E542K in culture (PMID: 26627007). 26627007
PIK3CA H1047L breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047L in culture (PMID: 26627007). 26627007
PIK3CA H1047L breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047L in culture (PMID: 26627007). 26627007
PIK3CA G1049R Advanced Solid Tumor sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA N345K breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA E542K breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E542K in culture (PMID: 26627007). 26627007
PIK3CA Q546K breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA Q546K breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA E545K breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA N345K breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA H1047R breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007
PIK3CA E545K breast cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA H1047R breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007
PIK3CA N345K breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA E542K breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E542K in culture (PMID: 26627007). 26627007
PIK3CA E542K breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E542K in culture (PMID: 26627007). 26627007
PIK3CA Q546K Advanced Solid Tumor sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed cell lines overexpressing PIK3CA Q546K in culture (PMID: 26627007). 26627007
PIK3CA E545K breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA N345K breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA N345K in culture (PMID: 26627007). 26627007
PIK3CA H1047R breast cancer sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007
PIK3CA H1047R Advanced Solid Tumor sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007
PIK3CA G1049R breast cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA E542K breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA E542K in culture (PMID: 26627007). 26627007
PIK3CA E545K Advanced Solid Tumor sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited survival of transformed cell lines overexpressing PIK3CA E545K in culture (PMID: 26627007). 26627007
PIK3CA G1049R breast cancer sensitive MK2206 Preclinical Actionable In a preclinical study, MK2206 inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA G1049R breast cancer sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA G1049R in culture (PMID: 26627007). 26627007
PIK3CA H1047L breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047L in culture (PMID: 26627007). 26627007
PIK3CA H1047R breast cancer sensitive Alpelisib Preclinical Actionable In a preclinical study, Alpelisib (BYL719) inhibited survival of transformed breast epithelial cell lines overexpressing PIK3CA H1047R in culture (PMID: 26627007). 26627007