Molecule Information

General Information of the Molecule (ID: Mol04368)

• 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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Alpelisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck cancer [ICD-11: 2D42.0] [1]

• Resistant Disease: Head and neck cancer [ICD-11: 2D42.0]
• Resistant Drug: Alpelisib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: Cal-33 cells; Tongue; Homo sapiens (Human); CVCL_1108
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: HSC-4 cells; Cervical lymph node; Homo sapiens (Human); CVCL_1289
• In Vitro Model: SAS cells; Oral; Homo sapiens (Human); CVCL_1675
• In Vitro Model: UT-SCC-5 cells; Head and Neck; Homo sapiens (Human); CVCL_7858
• In Vitro Model: UT-SCC-8 cells; Head and Neck; Homo sapiens (Human); CVCL_7869
• In Vitro Model: UT-SCC-14 cells; Head and Neck; Homo sapiens (Human); CVCL_7810
• In Vitro Model: UT-SCC-15 cells; Head and Neck; Homo sapiens (Human); CVCL_7811
• Experiment for Molecule Alteration: Whole exome sequencing assay; Western blot assay; Akt activity assay; 3D foci assay; Phosphorylation pathway analysis; Gene enrichment assay; Network analysis; Functional enrichment analysis
• Experiment for Drug Resistance: 3D colony formation assay
• Mechanism Description: We demonstrate that Alpelisib, Copanlisib and AZD8186 but not Idelalisib enhance radio- and radiochemosensitivity in the majority of HNSCC cell models (= responders) in a manner independent of PIK3CA mutation status. However, Alpelisib promotes MAPK signaling in non-responders compared to responders without profound impact on Akt, NFkappaB, TGFbeta, JAK/STAT signaling and DNA repair. Bioinformatic analyses identified unique gene mutations associated with extracellular matrix to be more frequent in non-responder cell models than in responders. Finally, we demonstrate that targeting of the cell adhesion molecule beta1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel beta1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.

References

• Ref 1: beta1 integrin mediates unresponsiveness to PI3Kalpha inhibition for radiochemosensitization of 3D HNSCC models. Biomed Pharmacother. 2024 Feb;171:116217.