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Ref Type Journal Article
PMID (34779417)
Authors Jin N, Keam B, Cho J, Lee MJ, Kim HR, Torosyan H, Jura N, Ng PK, Mills GB, Li H, Zeng Y, Barbash Z, Tarcic G, Kang H, Bauman JE, Kim MO, VanLandingham NK, Swaney DL, Krogan NJ, Johnson DE, Grandis JR
Title Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.
Journal The Journal of clinical investigation
Vol 131
Issue 22
Date 2021 Nov 15
URL
Abstract Text Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

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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 C420R missense gain of function PIK3CA C420R lies within the C2 PI3K-type domain of the Pik3ca protein (PMID: 17376864). 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 C604R missense gain of function PIK3CA C604R lies within the PIK helical domain of the Pik3ca protein (UniProt.org). C604R results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type Pik3ca (PMID: 34779417) and increased transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA C901F missense gain of function - predicted PIK3CA C901F lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). C901F results in increased cell proliferation and migration (PMID: 34779417) and transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417), and therefore, is predicted to result in a gain of Pik3ca protein function.
PIK3CA C905S missense unknown PIK3CA C905S lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). C905S results in increased levels of cell migration but similar levels of cell proliferation and phosphorylation of Akt to wild-type Pik3ca and is not transforming in culture (PMID: 34779417), and therefore, its effect on Pik3ca protein function is unknown.
PIK3CA C971R missense gain of function - predicted PIK3CA C971R lies within the PI3K/PI4K kinase domain of the Pik3ca protein (UniProt.org). C971R results in increased cell proliferation, viability, migration, and transformation ability compared to wild-type Pik3ca in in several cell lines in culture (PMID: 29533785, PMID: 34779417), and in another study results in increased PI3K pathway signaling and moderate growth compared to control (PMID: 23619167) but leads to Akt phosphorylation similar to wild-type Pik3ca in another study (PMID: 34779417), and therefore, is predicted to result in a gain of Pik3ca protein function.
PIK3CA E110del deletion gain of function - predicted PIK3CA E110del results in the deletion of an amino acid in the Pik3ca protein (UniProt.org). E110del results in Akt phosphorylation similar to wild-type Pik3ca in cell culture (PMID: 34779417), but leads to increased cell proliferation and migration (PMID: 34779417) and transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417), and therefore, is predicted to result in a gain of Pik3ca protein function.
PIK3CA E365V missense gain of function PIK3CA E365V lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). E365V results in increased cell proliferation, migration, and phosphorylation of Akt compared to wild-type Pik3ca, and is transforming in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA E418K missense gain of function PIK3CA E418K lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). E418K results in increased cell proliferation, migration, and increased phosphorylation of Akt compared to wild-type Pik3ca and is transforming in culture (PMID: 34779417).
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 E726K missense gain of function PIK3CA E726K does not lie within any known functional domains of the Pik3ca protein (UniProt.org). E726K results in increased cell proliferation and migration and increased Akt phosphorylation compared to wild-type Pik3ca in culture (PMID: 34779417) and increased transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA E81K missense unknown PIK3CA E81K lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). The functional effect of E81K is conflicting, as it results in cell proliferation, migration, and Akt phosphorylation similar to wild-type Pik3ca in culture and is not transforming in one study (PMID: 34779417), but in other studies it leads to decreased cell proliferation and cell viability (PMID: 29533785) and increased Akt phosphorylation, activation of Mtor signaling, and growth advantage in patient-derived dermal fibroblasts in culture (PMID: 25915946), and therefore, its effect on Pik3ca protein function is unknown.
PIK3CA E970K missense gain of function - predicted PIK3CA E970K lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). E970K results in phosphorylated Akt levels similar to wild-type Pik3ca, but increased proliferation and cell migration and is transforming in culture (PMID: 34779417), and therefore, is predicted to result in a gain of Pik3ca protein function.
PIK3CA G1007R missense gain of function PIK3CA G1007R lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). G1007R results in increased cell proliferation and migration and increased Akt phosphorylation compared to wild-type Pik3ca in culture (PMID: 34779417) and increased transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA G363A missense unknown PIK3CA G363A lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). The functional effect of G363A is conflicting, as it demonstrates increased PI3K pathway signaling and moderate growth in culture (PMID: 23619167, PMID: 28528867) and increased cell migration (PMID: 34779417), however in other studies, results in cell proliferation levels, cell viability, and Akt phosphorylation similar to wild-type Pik3ca (PMID: 29533785, PMID: 34779417) and is not transforming in culture (PMID: 34779417), and therefore, its effect on Pik3ca protein function is unknown.
PIK3CA G451R missense gain of function PIK3CA G451R lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). G451R results in increased cell proliferation and migration and increased Akt phosphorylation compared to wild-type Pik3ca in culture (PMID: 34779417) and increased transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA K111E missense gain of function PIK3CA K111E lies within the region linking the PI3K-ABD and PI3K-RBD domains of the Pik3ca protein (UniProt.org). K111E confers a gain of function on the Pik3ca protein as indicated by increased lipid kinase activity and phosphorylation of Akt in cell culture (PMID: 22949682, PMID: 21266528), increased cell proliferation and migration, and is transforming in culture (PMID: 29533785, PMID: 34779417).
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 M1040I missense no effect PIK3CA M1040I lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). M1040I results in evels of cell proliferation, migration, and phosphorylation of Akt similar to wild-type Pik3ca and is not transforming in culture (PMID: 34779417).
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 N1068Kfs*5 frameshift gain of function PIK3CA N1068Kfs*5 indicates a shift in the reading frame starting at the final amino acid of the Pik3ca protein, 1068, and terminating 5 residues downstream, resulting in extension of the Pik3ca protein length by 3 amino acids (UniProt.org). N1068Kfs*5 results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type Pik3ca (PMID: 34779417), and increased transformation ability in several different cell lines in culture (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 P104L missense gain of function PIK3CA P104L lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). P104L results in increased cell proliferation and migration and increased Akt phosphorylation compared to wild-type Pik3ca in culture (PMID: 34779417) and increased transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA Q546R missense gain of function - predicted PIK3CA Q546R lies within the PIK helical domain of the Pik3ca protein (UniProt.org). Q546R results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type Pik3ca in culture (PMID: 34779417) and increased cell survival and transforming ability in culture (PMID: 26627007, PMID: 29533785, PMID: 34779417).
PIK3CA Q75E missense gain of function PIK3CA Q75E lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). Q75E results in increased cell proliferation, migration, and increased phosphorylation of Akt compared to wild-type Pik3ca and is transforming in culture (PMID: 34779417).
PIK3CA R335G missense no effect PIK3CA R335G lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). R335G results in levels of cell proliferation, migration, and phosphorylation of Akt similar to wild-type Pik3ca and is not transforming in culture (PMID: 34779417).
PIK3CA R519G missense no effect PIK3CA R519G lies within the PIK helical domain of the Pik3ca protein (UniProt.org). R519G results in levels of cell proliferation, migration, and phosphorylation of Akt similar to wild-type Pik3ca and is not transforming in culture (PMID: 34779417).
PIK3CA R88Q missense gain of function PIK3CA R88Q lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). R88Q confers a gain of function to the Pik3ca protein as indicated by increased phosphorylation of downstream targets Akt and S6, increased cell proliferation and migration, and is transforming in culture (PMID: 18829572, PMID: 29533785, PMID: 34779417).
PIK3CA R975S missense unknown PIK3CA R975S lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). The functional effect of R975S is conflicting, as it results in cell proliferation, viability, migration, and Akt phosphorylation levels similar to wild-type Pik3ca (PMID: 29533785, PMID: 34779417), but modestly increased cell proliferation in another study (PMID: 23619167), and therefore, its effect on Pik3ca protein function is unknown.
PIK3CA V344G missense gain of function PIK3CA V344G lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). V344G results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type Pik3ca in culture (PMID: 34779417) and increased transformation ability in several different cell lines in culture (PMID: 29533785, PMID: 34779417).
PIK3CA V71I missense unknown PIK3CA V71I lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). V71I results in increased levels of colony formation but leads to levels of cell migration and phosphorylation of Akt similar to wild-type Pik3ca and is not transforming in culture (PMID: 34779417), and therefore, its effect on Pik3ca protein function is unknown.
PIK3CA W328S missense unknown PIK3CA W328S does not lie within any known functional domains of the Pik3ca protein (UniProt.org). W328S results in increased levels of cell proliferation but leads to levels of cell migration and phosphorylation of Akt similar to wild-type Pik3ca and is not transforming in culture (PMID: 34779417), and therefore, its effect on Pik3ca protein function is unknown.
PIK3CA Y606C missense no effect PIK3CA Y606C lies within the PIK helical domain of the Pik3ca protein (UniProt.org). Y606C results similar levels of cell proliferation, migration, and phosphorylation of Akt to wild-type Pik3ca and is not transforming in culture (PMID: 34779417).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA N345K head and neck squamous cell carcinoma predicted - sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, treatment with Piqray (alpelisib) resulted in inhibition of proliferation and increased apoptosis in a head and neck squamous cell carcinoma cell line expressing PIK3CA N345K in culture (PMID: 34779417). 34779417
PIK3CA M1043V head and neck squamous cell carcinoma predicted - sensitive Alpelisib Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with Piqray (alpelisib) resulted in inhibition of proliferation and increased apoptosis in a head and neck squamous cell carcinoma (HNSCC) cell line expressing PIK3CA M1043V in culture and led to inhibition of tumor growth and decreased phosphorylated Akt levels in a patient-derived xenograft (PDX) model of HNSCC with PIK3CA M1043V (PMID: 34779417). 34779417
PIK3CA Q75E head and neck squamous cell carcinoma predicted - sensitive Alpelisib Case Reports/Case Series Actionable In clinical case study, treatment with Piqray (alpelisib) resulted in a partial response with 73% tumor shrinkage in a patient with head and neck squamous cell carcinoma (HNSCC) harboring PIK3CA Q75E, and in a preclinical analysis, resulted in inhibition of proliferation and increased apoptosis in a HNSCC cell line expressing PIK3CA Q75E in culture (PMID: 34779417). 34779417