P110α
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| Location (UCSC) | Chr 3: 179.15 – 179.24 Mb | Chr 3: 32.45 – 32.52 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the
Its role was uncovered by molecular pathological epidemiology (MPE).[6]
Function
The involvement of p110α in human cancer has been hypothesized since 1995. Support for this hypothesis came from genetic and functional studies, including the discovery of common activating PIK3CA missense mutations in common human tumors.[8] It has been found to be oncogenic and is implicated in cervical cancers.[9] PIK3CA mutations are present in over one-third of breast cancers, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes (HER2 +). The three hotspot mutation positions (GLU542, GLU545, and HIS1047) have been widely reported till date.[10] While substantial preclinical data show an association with robust activation of the pathway and resistance to common therapies, clinical data do not indicate that such mutations are associated with high levels of pathway activation or with a poor prognosis. It is unknown whether the mutation predicts increased sensitivity to agents targeting the P3K pathway.[11]
PIK3CA participates in a complex interaction within the tumor microenvironment in this phenomenon.[12]
Clinical characteristics
Due to the association between p110α and cancer,[13] it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors.[14][15]
The presence of [a] PIK3CA mutation may predict response to aspirin therapy for colorectal cancer.[16][17]
Somatic activating mutations in PIK3CA are found in
PIK3CA-associated segmental overgrowth includes brain disorders such as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly. It is also associated with congenital, lipomatous overgrowth of vascular malformations, epidermal nevi and skeletal/spinal anomalies (CLOVES syndrome) and fibroadipose hyperplasia (FH). The conditions are caused by heterozygous (usually somatic mosaic) mutations.[20]
Inhibition
All PI 3-kinases are inhibited by the drugs wortmannin and LY294002 but wortmannin shows better efficiency than LY294002 on the hotspot mutation positions.[21][22]
Pharmacology
In September 2017 Copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.[23]
See also
Interactions
P110α has been shown to interact with:
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000121879 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027665 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 1322797.
- PMID 23792451.
- ^ "Entrez Gene: PIK3CA".
- PMID 20535651.
- PMID 10851074.
- PMID 27581627.
- PMID 25192370.
- PMID 24166520.
- S2CID 10147415.
- S2CID 568427.
- PMID 17997386.
- PMID 23094721.
- PMID 24062397.[permanent dead link]
- PMID 26637981.
- PMID 25681199.
- PMID 23946963.
- PMID 27581627.
- PMID 26827608.
- ^ "FDA approves new treatment for adults with relapsed follicular lymphoma". US Food and Drug Administration. September 14, 2017.
- PMID 12754211.
- PMID 12893243.
- PMID 12890670.
- PMID 14724584.
- PMID 10783161.
- PMID 8665852.
- PMID 14583609.
- PMID 8246987.
Further reading
- Foster FM, Traer CJ, Abraham SM, Fry MJ (August 2003). "The phosphoinositide (PI) 3-kinase family". Journal of Cell Science. 116 (Pt 15): 3037–40. PMID 12829733.
- Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY (March 2005). "Mutations of PIK3CA in gastric adenocarcinoma". BMC Cancer. 5: 29. PMID 15784156.
- Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, S2CID 83474940.
- Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut SJ, Tsui DW, Liu B, Dawson SJ, Abraham J, Northen H, Peden JF, Mukherjee A, Turashvili G, Green AR, McKinney S, Oloumi A, Shah S, Rosenfeld N, Murphy L, Bentley DR, Ellis IO, Purushotham A, Pinder SE, Børresen-Dale AL, Earl HM, Pharoah PD, Ross MT, Aparicio S, Caldas C (May 2016). "The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes". Nature Communications. 7: 11479. PMID 27161491.
