Molecule Information

General Information of the Molecule (ID: Mol04369)

• Name: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) ,Homo sapiens
• Synonyms: Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha; Phosphoinositide 3-kinase alpha ; Phosphoinositide-3-kinase catalytic alpha polypeptide; Serine/threonine protein kinase PIK3CA
• Molecule Type: Protein
• Gene Name: PIK3CA
• Gene ID: 5290
• Sequence:
  MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ
  LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGF
  A IGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELP
  KH IYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSE
  QLK LCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQ
  LPMD CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIY
  VRTGI YHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKG
  AKEEHC PLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCL
  ELEFDWF SSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLK
  AISTRDPL SEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWP
  PIKPEQAME LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLV
  RFLLKKALTN QRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAM
  EKLINLTDILK QEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEE
  CRIMSSAKRPLW LNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQ
  GLDLRMLPYGCLS IGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNK
  GEIYDAAIDLFTRS CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKF
  GYKRERVPFVLTQDF LIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSM
  MLGSGMPELQSFDDIA YIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIK
  QHALN
• Function: Phosphoinositide-3-kinase phosphorylatesphosphatidylinositol and its phosphorylated derivatives atposition 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP andPtdInsP2 to generatephosphatidylinositol 3,4,5-trisphosphate . PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1,activating signaling cascades involved in cell growth, survival,proliferation, motility and morphology. Participates in cellularsignaling in response to various growth factors. Involved in theactivation of AKT1 upon stimulation by receptor tyrosine kinasesligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved insignaling via insulin-receptor substrate proteins. Essential inendothelial cell migration during vascular development through VEGFAsignaling, possibly by regulating RhoA activity. Required for lymphaticvasculature development, possibly by binding to RAS and by activationby EGF and FGF2, but not by PDGF. Regulates invadopodia formationthrough the PDPK1-AKT1 pathway. Participates in cardiomyogenesis inembryonic stem cells through a AKT1 pathway. Participates invasculogenesis in embryonic stem cells through PDK1 and protein kinaseC pathway. In addition to its lipid kinase activity, it displays aserine-protein kinase activity that results in the autophosphorylationof the p85alpha regulatory subunit as well as phosphorylation of otherproteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possiblyothers . Plays a role in the positiveregulation of phagocytosis and pinocytosis .{ECO:0000250|UniProtKB:P42337, ECO:0000269|PubMed:15135396,ECO:0000269|PubMed:21708979, ECO:0000269|PubMed:23936502,ECO:0000269|PubMed:26593112, ECO:0000269|PubMed:28676499}.
• Uniprot ID: PK3CA_HUMAN
• Ensembl ID: ENSG000001218796
• HGNC ID: HGNC:8975

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Alpelisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Alpelisib
• Molecule Alteration: Mutation; E17K
• Experiment for Molecule Alteration: Cell-Free DNA extraction assay; ddPCR
• Mechanism Description: Although secondary?PIK3CA?mutations were previously reported to increase sensitivity to PI3Kalpha inhibitors, we identified emergent secondary resistance mutations in?PIK3CA?that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kalpha-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kalpha-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in?PIK3CA-mutated cancers.

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Alpelisib
• Molecule Alteration: Mutation; Q24K/L28M/R30Q/A92K RASs
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Cell-Free DNA extraction assay; ddPCR
• Mechanism Description: Although secondary?PIK3CA?mutations were previously reported to increase sensitivity to PI3Kalpha inhibitors, we identified emergent secondary resistance mutations in?PIK3CA?that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kalpha-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kalpha-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in?PIK3CA-mutated cancers.

References

• Ref 1: Allosteric PI3Kalpha Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations. Cancer Discov. 2024 Feb 8;14(2):227-239.