Molecule Information

General Information of the Molecule (ID: Mol00562)

• Name: PI3-kinase alpha (PIK3CA) ,Homo sapiens
• Synonyms: PI3-kinase subunit alpha; PI3K-alpha; PI3Kalpha; PtdIns-3-kinase subunit alpha; Phosphatidylinositol 4;5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha; PtdIns-3-kinase subunit p110-alpha; p110alpha; Phosphoinositide 3-kinase alpha; Phosphoinositide-3-kinase catalytic alpha polypeptide; Serine/threonine protein kinase PIK3CA
• Molecule Type: Protein
• Gene Name: PIK3CA
• Gene ID: 5290
• Location: chr3:179148114-179240093[+]
• Sequence:
  MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ
  LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFA
  IGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKH
  IYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLK
  LCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD
  CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGI
  YHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHC
  PLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWF
  SSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPL
  SEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME
  LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTN
  QRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILK
  QEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLW
  LNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLS
  IGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS
  CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRERVPFVLTQDF
  LIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIA
  YIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALN
• Function: Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). 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 cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others. Plays a role in the positive regulation of phagocytosis and pinocytosis.
• Uniprot ID: PK3CA_HUMAN
• Ensembl ID: ENSG00000121879
• 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

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 10 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Tongue squamous cell carcinoma [1]

• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PIk3CA signaling pathway; Regulation; hsa04211
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-203 expression is much lower in the clinical tongue cancer samples. In the surviving Tca8113 cells after cisplatin treatment, miR-203 expression was much lower. Delivery of miR-203 sensitized the Tca8113 cells to cisplatin induced cell death through downregulation of PIk3CA.

Erlotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [2]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Erlotinib
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Disease Class: EGFR-mutant non-small cell lung cancer [3]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Erlotinib
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutantalleles in association with emergence of therapy resistance. These included an activating mutation in PIk3CA.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: EGFR-mutant non-small cell lung cancer [4]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: MGB SNP detection kit assay; Mutation Detection assay
• Experiment for Drug Resistance: Digital PCR assay
• Mechanism Description: Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.

Disease Class: Non-small cell lung cancer [2]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Disease Class: EGFR-mutant non-small cell lung cancer [3]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutantalleles in association with emergence of therapy resistance. These included an activating mutation in PIk3CA.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Esophageal squamous cell carcinoma [5]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/survivin signaling pathway; Inhibition; hsa04151
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exogenous expression of miR 1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIk3CA protein expression levels. Furthermore, overexpression of miR 1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib.

Idelalisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Merkel cell carcinoma [6]

• Sensitive Disease: Merkel cell carcinoma [ICD-11: 2C34.0]
• Sensitive Drug: Idelalisib
• Molecule Alteration: Missense mutation; p.P471L (c.1412C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Molecule Alteration: Real-time PCR

Lapatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [7]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Lapatinib
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HER2-amplified breast cancer cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Multi-region sequencing assay; Single-cell sequencing assay
• Mechanism Description: Similarly, PTEN loss or PIk3CA mutation was found to lower the clinical benefit of lapatinib in HER2-amplified metastatic breast cancer and to be responsible for lapatinib resistance in breast cancer cell lines. Tumor-promoting mutations seem to be involved in three major biological processes: cell survival, sensitive to mutations in EGFR, HER2, PIk3CA, BRAF, PTEN, MYC and others; cell fate, influenced by mutations in APC, NOTCH, AR, GATA2, kLF4 and genomic stability, altered by mutations in TP53, ATM, BRCA1, BRCA2 and others.

Nimotuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Esophageal squamous cell carcinoma [8]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Resistant Drug: Nimotuzumab
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• Mechanism Description: NGS examination of this patient demonstrated that PIK3CA mutation and a RICTOR amplification might participate in primary and acquired resistance to nimotuzumab, respectively, via the PI3K/AKT/mTOR signaling pathway.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [9]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Missense mutation; p.E545K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.N345K (c.1035T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.N345K (c.1035T>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.Q546K (c.1636C>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.Q546K (c.1636C>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.H1047L (c.3140A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.H1047L (c.3140A>T) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.G1049R (c.3145G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.G1049R (c.3145G>C) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [10]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.N345K (c.1035T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.N345K (c.1035T>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [10]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [10]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.Q546K (c.1636C>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.Q546K (c.1636C>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [10]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [10]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.G1049R (c.3145G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.G1049R (c.3145G>C) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Trastuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [11]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female athymic nude xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the resistance of Trastuzumab by unusual activation of pro-survival pathway

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [12]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.E545K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: In patient #11, sequential biopsies showed three mutations that were not detected in the pretreatment biopsy, including an activating mutation in PIk3CA E545k readily explaining the resistance.

Clinical Trial Drug(s) 19 drug(s) in total

Buparlisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [13]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.N345I (c.1034A>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Disease Class: Breast adenocarcinoma [13]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.E39K (c.115G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Disease Class: Breast adenocarcinoma [13]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.E453K (c.1357G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Disease Class: Breast adenocarcinoma [13]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Disease Class: Breast adenocarcinoma [13]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Disease Class: Breast adenocarcinoma [13]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.G1049R (c.3145G>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast adenocarcinoma [14]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vivo Model: Athymic mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [15]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SQCLC SKMES-1 cells; Pleura; Homo sapiens (Human); CVCL_0630
• In Vitro Model: HCC2450 cells; Lung; Homo sapiens (Human); CVCL_5133
• In Vitro Model: H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Balb/c-Nude female xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Disease Class: Lung adenocarcinoma [15]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Buparlisib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SQCLC SKMES-1 cells; Pleura; Homo sapiens (Human); CVCL_0630
• In Vitro Model: HCC2450 cells; Lung; Homo sapiens (Human); CVCL_5133
• In Vitro Model: H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Balb/c-Nude female xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Capivasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Gastric adenocarcinoma [16]

• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Sensitive Drug: Capivasertib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Stomach; .
• In Vivo Model: GC xenograft (PDGCX) mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Disease Class: Gastrointestinal system cancer [16]

• Sensitive Disease: Gastrointestinal system cancer [ICD-11: 2C11.Y]
• Sensitive Drug: Capivasertib
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Stomach; .
• In Vivo Model: GC xenograft (PDGCX) mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Disease Class: Gastrointestinal system cancer [16]

• Sensitive Disease: Gastrointestinal system cancer [ICD-11: 2C11.Y]
• Sensitive Drug: Capivasertib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Stomach; .
• In Vivo Model: GC xenograft (PDGCX) mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Rigosertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Head and neck squamous cell carcinoma [17]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: Rigosertib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HNSCC cells; Neck; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Sulforhodamine B colorimetric assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of Rigosertib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [18]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Rigosertib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS/RAF/MEK/ERK signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: WM1617 cells; Lymph node; Homo sapiens (Human); CVCL_6791
• In Vivo Model: Female nu/nu mouse PDX model; Mus musculus
• Mechanism Description: Rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that rigosertib binds to the RBDs of Ral-GDS and PI3Ks.

Disease Class: Solid tumour/cancer [18]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Rigosertib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS/RAF/MEK/ERK signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: WM1617 cells; Lymph node; Homo sapiens (Human); CVCL_6791
• In Vivo Model: Female nu/nu mouse PDX model; Mus musculus
• Mechanism Description: Rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that rigosertib binds to the RBDs of Ral-GDS and PI3Ks.

Saracatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [19]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Saracatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-19b-3p increases saracatinib sensitivity by inhibiting the PI3k/Akt pathway and miR-19b-3p directly bound to the 3'-UTR of PIk3CA and inhibited PIk3CA expression.

Taselisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Head and neck squamous cell carcinoma [20]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: Taselisib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• In Vitro Model: UPCI-SCC-90 cells; Tongue; Homo sapiens (Human); CVCL_1899
• In Vitro Model: UPCI-SCC-154 cells; Tongue; Homo sapiens (Human); CVCL_2230
• In Vitro Model: UM-SCC-47 cells; Tongue; Homo sapiens (Human); CVCL_7759
• In Vitro Model: UM-SCC-104 cells; Cervical lymph node; Homo sapiens (Human); CVCL_7712
• In Vitro Model: UD-SCC-2 cells; Neck; Homo sapiens (Human); CVCL_E325
• In Vitro Model: SNU46 cells; Larynx; Homo sapiens (Human); CVCL_5063
• In Vitro Model: SNU cells; Stomach; Homo sapiens (Human); CVCL_0099
• In Vitro Model: HSC-4 cells; Cervical lymph node; Homo sapiens (Human); CVCL_1289
• In Vitro Model: HSC-3 cells; Cervical lymph node; Homo sapiens (Human); CVCL_1288
• In Vitro Model: HSC-2 cells; Cervical lymph node; Homo sapiens (Human); CVCL_1287
• In Vitro Model: Detroit 562 cells; Pleural effusion; Homo sapiens (Human); CVCL_1171
• In Vitro Model: Cal-33 cells; Tongue; Homo sapiens (Human); CVCL_1108
• In Vitro Model: BICR-31 cells; Tongue; Homo sapiens (Human); CVCL_2312
• In Vitro Model: BICR-22 cells; Lymph node; Homo sapiens (Human); CVCL_2310
• In Vitro Model: BICR-18 cells; Lymph Node; Homo sapiens (Human); CVCL_2309
• In Vitro Model: BICR-16 cells; Tongue; Homo sapiens (Human); CVCL_2308
• In Vitro Model: 93-VU-147T cells; Oral cavity; Homo sapiens (Human); CVCL_L895
• In Vivo Model: Nu/Nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Crystal violet staining assay

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [21]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Taselisib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vivo Model: SCID beige mouse PDX model; Mus musculus

Disease Class: Lung adenocarcinoma [21]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Taselisib
• Molecule Alteration: Missense mutation; p.H1047X (c.3139_3141)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vivo Model: SCID beige mouse PDX model; Mus musculus

Apitolisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Malignant pleural mesothelioma [22]

• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Sensitive Drug: Apitolisib
• Molecule Alteration: Missense mutation; p.R88Q (c.263G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: .; .
• Experiment for Molecule Alteration: DxS allele-specific PCR; qRT-PCR assays; Sanger sequencing assay
• Experiment for Drug Resistance: CTCAE assay

Disease Class: Solid tumour/cancer [22]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Apitolisib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DxS allele-specific PCR; qRT-PCR assays; Sanger sequencing assay
• Experiment for Drug Resistance: CTCAE assay

Disease Class: Head and neck squamous cell carcinoma [22]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: Apitolisib
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DxS allele-specific PCR; qRT-PCR assays; Sanger sequencing assay
• Experiment for Drug Resistance: CTCAE assay

LY-3023414

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute lymphocytic leukemia [23]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: LY-3023414
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: NCI-H1734 cells; Lung; Homo sapiens (Human); CVCL_1491
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: NCI-H226 cells; Pleural effusion; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCI-H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: NCI-H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI- H460 cells; Pleural effusion; Homo sapiens (Human); CVCL_0459
• In Vitro Model: ACC-MESO-4 cells; Pleural epithelium; Homo sapiens (Human); CVCL_5114
• In Vitro Model: ACC-MESO-1 cells; Pleural epithelium; Homo sapiens (Human); CVCL_5113
• Experiment for Drug Resistance: CellTitre-Glo assay; Caspase-Glo 3/7 assay

Disease Class: Lung adenocarcinoma [23]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: LY-3023414
• Molecule Alteration: Missense mutation; p.G118D (c.353G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: NCI-H1734 cells; Lung; Homo sapiens (Human); CVCL_1491
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: NCI-H226 cells; Pleural effusion; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCI-H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: NCI-H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI- H460 cells; Pleural effusion; Homo sapiens (Human); CVCL_0459
• In Vitro Model: ACC-MESO-4 cells; Pleural epithelium; Homo sapiens (Human); CVCL_5114
• In Vitro Model: ACC-MESO-1 cells; Pleural epithelium; Homo sapiens (Human); CVCL_5113
• Experiment for Drug Resistance: CellTiter-Glo assay; Caspase-Glo 3/7 assay

Miransertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast adenocarcinoma [24]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Miransertib
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of Miransertib by aberration of the drug's therapeutic target

Disease Class: Breast adenocarcinoma [24]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Miransertib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of Miransertib by aberration of the drug's therapeutic target

Disease Class: Breast adenocarcinoma [24]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Miransertib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Miransertib by aberration of the drug's therapeutic target

MK-2206

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast adenocarcinoma [25]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK-2206
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of MK-2206 by aberration of the drug's therapeutic target

PF-04691502

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Ovarian cancer [26]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: PF-04691502
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293-MSR cells; Fetal kidney; Homo sapiens (Human); CVCL_KS18
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of PF-04691502 by aberration of the drug's therapeutic target

Pictilisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [27]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Pictilisib
• Molecule Alteration: Missense mutation; p.D549Y (c.1645G>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Activation; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [25]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Pictilisib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Female NCR nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: PCR DNA sequencing assay
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Voxtalisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast adenocarcinoma [28]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Voxtalisib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: Ramos cells; Ascites; Homo sapiens (Human); CVCL_0597
• In Vitro Model: OVCAR-3 cells; Ascites; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ViaLight HS assay; Apo-ONE Homogeneous Caspase-3/7 assay; Soft agar assay

CH-5132799

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Prostate cancer [29]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: CH-5132799
• Molecule Alteration: Missense mutation; p.Q546R (c.1637A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: GXF97 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.Q546R (c.1637A>G) in gene PIK3CA cause the sensitivity of CH-5132799 by aberration of the drug's therapeutic target

Disease Class: Breast adenocarcinoma [29]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: CH-5132799
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: GXF97 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of CH-5132799 by aberration of the drug's therapeutic target

Disease Class: Breast adenocarcinoma [29]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: CH-5132799
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: GXF97 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of CH-5132799 by aberration of the drug's therapeutic target

Disease Class: Endometrial adenocarcinoma [29]

• Sensitive Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Sensitive Drug: CH-5132799
• Molecule Alteration: Missense mutation; p.H1047Y (c.3139C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: GXF97 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H1047Y (c.3139C>T) in gene PIK3CA cause the sensitivity of CH-5132799 by aberration of the drug's therapeutic target

Disease Class: Ovarian cancer [29]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: CH-5132799
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: GXF97 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of CH-5132799 by aberration of the drug's therapeutic target

Disease Class: Ovarian cancer [30]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: CH-5132799
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ARRAY system assay
• Experiment for Drug Resistance: Presto blue assay

BAY1125976

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [31]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: BAY1125976
• Molecule Alteration: Missense mutation; p.K111N (c.333G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: T47D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.K111N (c.333G>C) in gene PIK3CA cause the sensitivity of BAY1125976 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [31]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: BAY1125976
• Molecule Alteration: Missense mutation; p.P539R (c.1616C>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: T47D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.P539R (c.1616C>G) in gene PIK3CA cause the sensitivity of BAY1125976 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [31]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: BAY1125976
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: T47D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of BAY1125976 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [31]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: BAY1125976
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: T47D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of BAY1125976 by unusual activation of pro-survival pathway

LY-294002

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Oesophagus adenocarcinoma [32]

• Sensitive Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Sensitive Drug: LY-294002
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TE cells; Eye; Oreochromis mossambicus (Mozambique tilapia); CVCL_YD05
• In Vitro Model: KYSE cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of LY-294002 by aberration of the drug's therapeutic target

LY2780301

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Colon cancer [33]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: LY2780301
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: .; .
• In Vivo Model: Female athymic nude-Foxn1 nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Pharmacokinetic studies; Pharmacokinetic studies; Antitumor activity

M2698

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [34]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: M2698
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: JIMT-1 cells; Breast; Homo sapiens (Human); CVCL_2077
• In Vitro Model: HCC1419 cells; Breast; Homo sapiens (Human); CVCL_1251
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SRB staining assay
• Mechanism Description: M2698 blocked p70S6K to provide potent PAM pathway inhibition while simultaneously targeting Akt to overcome the compensatory feedback loop.

Perifosine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [35]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Perifosine
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of Perifosine by unusual activation of pro-survival pathway

Disease Class: Thyroid gland cancer [35]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Perifosine
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Perifosine by unusual activation of pro-survival pathway

VS-5584

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colon cancer [36]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: VS-5584
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNU869 cells; Biliary tract; Homo sapiens (Human); CVCL_5101
• In Vitro Model: SNU478 cells; Biliary tract; Homo sapiens (Human); CVCL_5065
• In Vitro Model: SNU308 cells; Biliary tract; Homo sapiens (Human); CVCL_5048
• In Vitro Model: SNU245 cells; Biliary tract; Homo sapiens (Human); CVCL_5038
• In Vitro Model: SNU1196 cells; Biliary tract; Homo sapiens (Human); CVCL_5015
• In Vitro Model: SNU1079 cells; Biliary tract; Homo sapiens (Human); CVCL_5008
• In Vitro Model: SET-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: Athymic BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of VS-5584 by aberration of the drug's therapeutic target

Discontinued Drug(s) 2 drug(s) in total

Rociletinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [37], [38]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Rociletinib
• Molecule Alteration: Missense mutation; p.E545K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Disease Class: Non-small cell lung cancer [37], [38]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Rociletinib
• Molecule Alteration: Missense mutation; p.E542K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

S-1

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: EGFR-mutant non-small cell lung cancer [4]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: S-1
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: MGB SNP detection kit assay; Mutation Detection assay
• Experiment for Drug Resistance: Digital PCR assay
• Mechanism Description: Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.

Preclinical Drug(s) 20 drug(s) in total

A66

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [39]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: A66
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Skin; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the resistance of A66 by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [39]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: A66
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Skin; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of A66 by aberration of the drug's therapeutic target

Disease Class: Ovarian cancer [39]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: A66
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Skin; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of A66 by aberration of the drug's therapeutic target

ARQ 751

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast adenocarcinoma [24]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: ARQ 751
• Molecule Alteration: Missense mutation; p.K111N (c.333G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.K111N (c.333G>C) in gene PIK3CA cause the sensitivity of ARQ 751 by aberration of the drug's therapeutic target

Disease Class: Breast adenocarcinoma [24]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: ARQ 751
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of ARQ 751 by aberration of the drug's therapeutic target

Disease Class: Breast adenocarcinoma [24]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: ARQ 751
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-60 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: CAL-120 cells; Pleural effusion; Homo sapiens (Human); CVCL_1104
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: B16F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vivo Model: Female NMRI (nu/nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of ARQ 751 by aberration of the drug's therapeutic target

AZD-8835

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: ER positive breast cancer [40]

• Sensitive Disease: ER positive breast cancer [ICD-11: 2C60.6]
• Sensitive Drug: AZD-8835
• Molecule Alteration: Missense mutation; p.K111N (c.333G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vivo Model: Female Swiss athymic nude mouse PDX model; Mus musculus

Disease Class: ER positive breast cancer [40]

• Sensitive Disease: ER positive breast cancer [ICD-11: 2C60.6]
• Sensitive Drug: AZD-8835
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vivo Model: Female Swiss athymic nude mouse PDX model; Mus musculus

AZD5363/Trastuzumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [41]

• Sensitive Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Sensitive Drug: AZD5363/Trastuzumab
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of AZD5363 + Trastuzumab by unusual activation of pro-survival pathway

Cisplatin/Pictilisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Sensitive Drug: Cisplatin/Pictilisib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

CYH33

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [42]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: CYH33
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vivo Model: MMTV-Cre mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry analysis
• Experiment for Drug Resistance: Sulforhodamine B assay; FACS assay
• Mechanism Description: Sensitivity to CYH33 has been further revealed to be associated with induction of G1 phase arrest and simultaneous inhibition of Akt and ERK. Sensitivity of patient-derived xenograft to CYH33 was also positively correlated with decrease in phosphorylated ERK. Taken together, CYH33 is a promising PI3Kalpha inhibitor for breast cancer treatment and decrease in ERK phosphorylation may indicate its efficacy, which provides useful clues for rational design of the ongoing clinical trials.

Disease Class: Breast adenocarcinoma [42]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: CYH33
• Molecule Alteration: Missense mutation; p.P539R (c.1616C>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vivo Model: MMTV-Cre mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry analysis
• Experiment for Drug Resistance: Sulforhodamine B assay; FACS assay
• Mechanism Description: Sensitivity to CYH33 has been further revealed to be associated with induction of G1 phase arrest and simultaneous inhibition of Akt and ERK. Sensitivity of patient-derived xenograft to CYH33 was also positively correlated with decrease in phosphorylated ERK. Taken together, CYH33 is a promising PI3Kalpha inhibitor for breast cancer treatment and decrease in ERK phosphorylation may indicate its efficacy, which provides useful clues for rational design of the ongoing clinical trials.

Disease Class: Breast adenocarcinoma [42]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: CYH33
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vivo Model: MMTV-Cre mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry analysis
• Experiment for Drug Resistance: Sulforhodamine B assay; FACS assay
• Mechanism Description: Sensitivity to CYH33 has been further revealed to be associated with induction of G1 phase arrest and simultaneous inhibition of Akt and ERK. Sensitivity of patient-derived xenograft to CYH33 was also positively correlated with decrease in phosphorylated ERK. Taken together, CYH33 is a promising PI3Kalpha inhibitor for breast cancer treatment and decrease in ERK phosphorylation may indicate its efficacy, which provides useful clues for rational design of the ongoing clinical trials.

DHM25

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [43]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: DHM25
• Molecule Alteration: Missense mutation; p.K111N (c.333G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: T47-D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vivo Model: NOD/SCID/gamac null mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Disease Class: Breast adenocarcinoma [43]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: DHM25
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: T47-D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vivo Model: NOD/SCID/gamac null mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Disease Class: Breast adenocarcinoma [43]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: DHM25
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: T47-D cells; Pleural effusion; Homo sapiens (Human); CVCL_0553
• In Vivo Model: NOD/SCID/gamac null mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

DS-7423

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Ovarian cancer [44]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: DS-7423
• Molecule Alteration: Missense mutation; p.C420R (c.1258T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: TOV-21 cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: RMG-I cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVKATE cells; Ovary; Homo sapiens (Human); CVCL_3110
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OV1063 cells; Ascites; Homo sapiens (Human); CVCL_4366
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: CCK-8 assay

Disease Class: Ovarian cancer [44]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: DS-7423
• Molecule Alteration: Missense mutation; p.E545V (c.1634A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21 cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: SKOV4 cells; Uterus; Homo sapiens (Human); CVCL_X008
• In Vitro Model: RMG-I cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVKATE cells; Ovary; Homo sapiens (Human); CVCL_3110
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OV1063 cells; Ascites; Homo sapiens (Human); CVCL_4366
• In Vitro Model: SKOV4 cells; Uterus; Homo sapiens (Human); CVCL_X008
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: CCK-8 assay

MK2206

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.N345K (c.1035T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.N345K (c.1035T>G) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.Q546K (c.1636C>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.Q546K (c.1636C>A) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.H1047L (c.3140A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.H1047L (c.3140A>T) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Breast adenocarcinoma [10]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.G1049R (c.3145G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.G1049R (c.3145G>C) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Disease Class: Thyroid gland cancer [45]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

MK2206/Temsirolimus

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [45]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: MK2206/Temsirolimus
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of MK2206 + Temsirolimus by unusual activation of pro-survival pathway

Disease Class: Thyroid gland cancer [45]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: MK2206/Temsirolimus
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of MK2206 + Temsirolimus by unusual activation of pro-survival pathway

PD-0325901/Pictilisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [46]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: PD-0325901/Pictilisib
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Female athymic CD1 mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Tumor volume measurement assay

PI103

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [47]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: PI103
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [47]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: PI103
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data

Pictilisib/Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Sensitive Drug: Pictilisib/Sorafenib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

Pilaralisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [48]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Pilaralisib
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: Ramos cells; Ascites; Homo sapiens (Human); CVCL_0597
• In Vitro Model: OVCAR-3 cells; Ascites; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ViaLight HS assay; Apo-ONE Homogeneous Caspase-3/7 assay; Soft agar assay

PKI-402

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [49]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: PKI-402
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: NCI-H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: NCI- H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_1483
• In Vitro Model: 786-0 cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of PKI-402 by aberration of the drug's therapeutic target

PW12

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Cervical cancer [50]

• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Sensitive Drug: PW12
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of PW12 by aberration of the drug's therapeutic target

SHR-A1307

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck squamous cell carcinoma [51]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: SHR-A1307
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: DiFi cells; Colon; Homo sapiens (Human); CVCL_6895
• In Vitro Model: Detroit562 cells; Pleural effusion; Homo sapiens (Human); CVCL_1171
• In Vitro Model: Colo-205 cells; Ascites; Homo sapiens (Human); CVCL_0218
• In Vivo Model: Female BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Sirolimus/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck squamous cell carcinoma [52]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: Sirolimus/Trametinib
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: UM-SCC-17B cells; Cervical lymph node; Homo sapiens (Human); CVCL_7725
• In Vitro Model: Detroit 562 cells; Pleural effusion; Homo sapiens (Human); CVCL_1171
• In Vivo Model: Athymic nude mouse tumor xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Alamar blue cell viability reagent assay
• Mechanism Description: mTOR and MEK inhibition display a synergistic growth inhibitory activity in HNSCC cells genetically engineered to express activating KRAS and PIK3CA mutations. Antitumoral activity of the rapamycin and trametinib combination therapy increase in genetically engineered HNSCC cells expressing activating RAS or PIK3CA mutations

WYE-125132

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [53]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: WYE-125132
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: Rat1 cells; Whole embryo; Rattus norvegicus (Rat); CVCL_0492
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of WYE-125132 by unusual activation of pro-survival pathway

YM-024

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [54]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: YM-024
• Molecule Alteration: Missense mutation; p.H1047Y (c.3139C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SK-MG-26 cell; N.A.; Homo sapiens (Human); CVCL_D701
• In Vitro Model: SK-MG-17 cells; N.A.; Homo sapiens (Human); CVCL_8574
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 AQueous assay; Soft-agar colony formation assay

Investigative Drug(s) 7 drug(s) in total

Alpelisib/Fulvestrant

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.C420R (c.1258T>C)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.E545A (c.1634A>C)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.E545G (c.1634A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.E545D (c.1635G>C)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.Q546E (c.1636C>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.Q546R (c.1637A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.H1047Y (c.3139C>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: HER2 negative breast cancer [55]

• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Sensitive Drug: Alpelisib/Fulvestrant
• Molecule Alteration: Missense mutation; p.H1047L (c.3140A>T)
• Experimental Note: Identified from the Human Clinical Data

Bevacizumab/Temsirolimus

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [56]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Bevacizumab/Temsirolimus
• Molecule Alteration: Missense mutation; p.H1047X (c.3139_3141)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.H1047X (c.3139_3141) in gene PIK3CA cause the resistance of Bevacizumab + Temsirolimus by unusual activation of pro-survival pathway

Buparlisib/Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [57]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Buparlisib/Paclitaxel
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Identified from the Human Clinical Data

Gemcitabine/LY2780301

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cervical cancer [58]

• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Sensitive Drug: Gemcitabine/LY2780301
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151

HER2 inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [59], [60]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: HER2 inhibitors
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Qubit HS dsDNA assay; Illumina sequencing assay; Sanger sequencing assay
• Mechanism Description: PIk3CA mutations may have independent driver properties in a HER2+ context and have been implicated in resistance to anti-HER2 therapies.

PI3K pathway inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [61]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: PI3K pathway inhibitors
• Molecule Alteration: Copy number gain; .
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter Glo luminescence assay; PathScan RTK signaling antibody array assay

PKI-587

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [62]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: PKI-587
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: HTB44 cells; Kidney; Homo sapiens (Human); N.A.
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: 786-0 cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Disease Class: Breast adenocarcinoma [62]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: PKI-587
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: HTB44 cells; Kidney; Homo sapiens (Human); N.A.
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: 786-0 cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Disease Class: Head and neck squamous cell carcinoma [63]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: PKI-587
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UMSCC cells; Oral cavity; Homo sapiens (Human); CVCL_7707
• In Vivo Model: SCID/NCr-Balb/c mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; qPCR
• Experiment for Drug Resistance: XTT assay

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.99E-16; Fold-change: 2.52E-01; Z-score: 4.65E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.60E-01; Fold-change: 5.84E-01; Z-score: 1.44E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.07E-05; Fold-change: 9.05E-01; Z-score: 1.91E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.15E-08; Fold-change: 1.75E+00; Z-score: 4.45E+00

Esophageal cancer [ICD-11: 2B70]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Esophagus
• The Specified Disease: Esophageal cancer
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.86E-01; Fold-change: -1.85E-01; Z-score: -5.12E-01

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.13E-01; Fold-change: 1.71E-01; Z-score: 2.92E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.18E-01; Fold-change: 3.73E-02; Z-score: 1.07E-01

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.96E-12; Fold-change: 1.58E-01; Z-score: 5.08E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.93E-01; Fold-change: 6.10E-03; Z-score: 1.55E-02

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.17E-13; Fold-change: -2.41E-01; Z-score: -7.91E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.76E-11; Fold-change: -3.01E-01; Z-score: -7.03E-01

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.70E-01; Fold-change: -1.51E-01; Z-score: -3.12E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.59E-38; Fold-change: -6.47E-01; Z-score: -1.11E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.29E-03; Fold-change: -4.33E-01; Z-score: -7.01E-01

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.39E-01; Fold-change: -1.90E-02; Z-score: -3.32E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.18E-04; Fold-change: 5.53E-01; Z-score: 1.13E+00

Cervical cancer [ICD-11: 2C77]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Cervix uteri
• The Specified Disease: Cervical cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.32E-05; Fold-change: 4.20E-01; Z-score: 1.10E+00

Prostate cancer [ICD-11: 2C82]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Prostate
• The Specified Disease: Prostate cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.43E-02; Fold-change: 9.14E-01; Z-score: 9.00E-01

Bladder cancer [ICD-11: 2C94]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bladder tissue
• The Specified Disease: Bladder cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.42E-12; Fold-change: -1.06E+00; Z-score: -7.76E+00

Thyroid cancer [ICD-11: 2D10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Thyroid
• The Specified Disease: Thyroid cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.40E-01; Fold-change: 3.75E-02; Z-score: 1.20E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.23E-03; Fold-change: 1.42E-01; Z-score: 4.14E-01

References

• Ref 1: miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer. Biochem Biophys Res Commun. 2016 Apr 29;473(2):382-7. doi: 10.1016/j.bbrc.2016.02.105. Epub 2016 Mar 3.
• Ref 2: Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1.
• Ref 3: Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
• Ref 4: Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1. Onco Targets Ther. 2016 Aug 24;9:5287-95. doi: 10.2147/OTT.S105976. eCollection 2016.
• Ref 5: MicroRNA-1 inhibits tumorigenicity of esophageal squamous cell carcinoma and enhances sensitivity to gefitinib. Oncol Lett. 2018 Jan;15(1):963-971. doi: 10.3892/ol.2017.7378. Epub 2017 Nov 9.
• Ref 6: Response to Idelalisib in a Patient with Stage IV Merkel-Cell CarcinomaN Engl J Med. 2015 Oct 15;373(16):1580-2. doi: 10.1056/NEJMc1507446.
• Ref 7: Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene. 2015 Jul;34(28):3617-26. doi: 10.1038/onc.2014.314. Epub 2014 Sep 29.
• Ref 8: Case Report: Primary and Acquired Resistance Mechanisms of Nimotuzumab in Advanced Esophageal Squamous Cell Carcinoma Revealed by Targeted Sequencing .Front Oncol. 2020 Oct 29;10:574523. doi: 10.3389/fonc.2020.574523. eCollection 2020. 10.3389/fonc.2020.574523
• Ref 9: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 10: Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare MutationsCancer Res. 2015 Dec 15;75(24):5341-54. doi: 10.1158/0008-5472.CAN-15-1654. Epub 2015 Dec 1.
• Ref 11: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutationsCancer Res. 2008 Oct 1;68(19):8022-30. doi: 10.1158/0008-5472.CAN-08-1385.
• Ref 12: Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res. 2015 May;28(3):318-23. doi: 10.1111/pcmr.12347. Epub 2015 Jan 7.
• Ref 13: Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patientsNat Commun. 2018 Apr 10;9(1):1357. doi: 10.1038/s41467-018-03867-9.
• Ref 14: The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activationSci Transl Med. 2017 May 24;9(391):eaal4682. doi: 10.1126/scitranslmed.aal4682.
• Ref 15: Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene AlterationsMol Cancer Ther. 2015 Aug;14(8):1916-27. doi: 10.1158/1535-7163.MCT-14-0892. Epub 2015 May 26.
• Ref 16: The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to TaxotereJ Transl Med. 2013 Oct 2;11:241. doi: 10.1186/1479-5876-11-241.
• Ref 17: The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomasMol Cancer Ther. 2013 Oct;12(10):1994-2005. doi: 10.1158/1535-7163.MCT-13-0206. Epub 2013 Jul 19.
• Ref 18: A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block SignalingCell. 2016 Apr 21;165(3):643-55. doi: 10.1016/j.cell.2016.03.045.
• Ref 19: miR-19b-3p inhibits breast cancer cell proliferation and reverses saracatinib-resistance by regulating PI3K/Akt pathway. Arch Biochem Biophys. 2018 May 1;645:54-60. doi: 10.1016/j.abb.2018.03.015. Epub 2018 Mar 14.
• Ref 20: Taselisib (GDC-0032), a Potent Beta-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA AlterationsClin Cancer Res. 2016 Apr 15;22(8):2009-19. doi: 10.1158/1078-0432.CCR-15-2245. Epub 2015 Nov 20.
• Ref 21: Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid TumorsCancer Discov. 2017 Jul;7(7):704-715. doi: 10.1158/2159-8290.CD-16-1080. Epub 2017 Mar 22.
• Ref 22: Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid TumorsClin Cancer Res. 2016 Jun 15;22(12):2874-84. doi: 10.1158/1078-0432.CCR-15-2225. Epub 2016 Jan 19.
• Ref 23: Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor GrowthMol Cancer Ther. 2016 Oct;15(10):2344-2356. doi: 10.1158/1535-7163.MCT-15-0996. Epub 2016 Jul 20.
• Ref 24: Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092PLoS One. 2015 Oct 15;10(10):e0140479. doi: 10.1371/journal.pone.0140479. eCollection 2015.
• Ref 25: PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model systemClin Cancer Res. 2013 Oct 1;19(19):5413-22. doi: 10.1158/1078-0432.CCR-13-0884. Epub 2013 Jul 25.
• Ref 26: PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activityMol Cancer Ther. 2011 Nov;10(11):2189-99. doi: 10.1158/1535-7163.MCT-11-0185. Epub 2011 Jul 12.
• Ref 27: The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder CancerClin Cancer Res. 2017 Nov 1;23(21):6580-6591. doi: 10.1158/1078-0432.CCR-17-0033. Epub 2017 Aug 14.
• Ref 28: Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathwayMol Cancer Ther. 2014 May;13(5):1078-91. doi: 10.1158/1535-7163.MCT-13-0709. Epub 2014 Mar 14.
• Ref 29: The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutationsClin Cancer Res. 2011 May 15;17(10):3272-81. doi: 10.1158/1078-0432.CCR-10-2882. Epub 2011 May 10.
• Ref 30: First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancerClin Cancer Res. 2014 Dec 1;20(23):5908-17. doi: 10.1158/1078-0432.CCR-14-1315. Epub 2014 Sep 17.
• Ref 31: BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse modelsInt J Cancer. 2017 Jan 15;140(2):449-459. doi: 10.1002/ijc.30457. Epub 2016 Oct 20.
• Ref 32: PIK3CA mutation status in Japanese esophageal squamous cell carcinomaJ Surg Res. 2008 Apr;145(2):320-6. doi: 10.1016/j.jss.2007.03.044. Epub 2008 Feb 11.
• Ref 33: A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancerInvest New Drugs. 2015 Jun;33(3):710-9. doi: 10.1007/s10637-015-0241-7. Epub 2015 Apr 24.
• Ref 34: M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrierAm J Cancer Res. 2016 Mar 15;6(4):806-18. eCollection 2016.
• Ref 35: Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycinCancer Res. 2009 Sep 15;69(18):7311-9. doi: 10.1158/0008-5472.CAN-09-1077. Epub 2009 Aug 25.
• Ref 36: VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancerMol Cancer Ther. 2013 Feb;12(2):151-61. doi: 10.1158/1535-7163.MCT-12-0466. Epub 2012 Dec 27.
• Ref 37: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016 Jun 10;7:11815. doi: 10.1038/ncomms11815.
• Ref 38: Tumor Evolution as a Therapeutic Target. Cancer Discov. 2017 Jul 20. doi: 10.1158/2159-8290.CD-17-0343. Online ahead of print.
• Ref 39: A drug targeting only p110Alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell typesBiochem J. 2011 Aug 15;438(1):53-62. doi: 10.1042/BJ20110502.
• Ref 40: Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3KAlpha and PI3K Delta, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast CancersMol Cancer Ther. 2016 May;15(5):877-89. doi: 10.1158/1535-7163.MCT-15-0687. Epub 2016 Feb 2.
• Ref 41: Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic backgroundMol Cancer Ther. 2012 Apr;11(4):873-87. doi: 10.1158/1535-7163.MCT-11-0824-T. Epub 2012 Jan 31.
• Ref 42: Decrease in phosphorylated ERK indicates the therapeutic efficacy of a clinical PI3KAlpha-selective inhibitor CYH33 in breast cancerCancer Lett. 2018 Oct 1;433:273-282. doi: 10.1016/j.canlet.2018.07.011. Epub 2018 Jul 9.
• Ref 43: A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer CellsJ Med Chem. 2015 Aug 27;58(16):6559-73. doi: 10.1021/acs.jmedchem.5b00991. Epub 2015 Aug 14.
• Ref 44: Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clear cell adenocarcinoma by the dual PI3K/mTOR inhibitor DS-7423PLoS One. 2014 Feb 4;9(2):e87220. doi: 10.1371/journal.pone.0087220. eCollection 2014.
• Ref 45: The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathwayJ Clin Endocrinol Metab. 2011 Apr;96(4):E577-85. doi: 10.1210/jc.2010-2644. Epub 2011 Feb 2.
• Ref 46: The enhanced in vivo activity of the combination of a MEK and a PI3K inhibitor correlates with [18F]-FLT PET in human colorectal cancer xenograft tumour-bearing micePLoS One. 2013 Dec 10;8(12):e81763. doi: 10.1371/journal.pone.0081763. eCollection 2013.
• Ref 47: A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cellsInt J Mol Med. 2009 Jul;24(1):97-101. doi: 10.3892/ijmm_00000212.
• Ref 48: The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor ModelsMol Cancer Ther. 2015 Apr;14(4):931-40. doi: 10.1158/1535-7163.MCT-14-0833. Epub 2015 Jan 30.
• Ref 49: Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitorMol Cancer Ther. 2010 Apr;9(4):976-84. doi: 10.1158/1535-7163.MCT-09-0954. Epub 2010 Apr 6.
• Ref 50: High levels of p110Delta PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110 Delta inhibitors through PTEN activationFASEB J. 2012 Jun;26(6):2498-508. doi: 10.1096/fj.11-198192. Epub 2012 Mar 5.
• Ref 51: Discovery of A Novel EGFR-Targeting Antibody-Drug Conjugate, SHR-A1307, for the Treatment of Solid Tumors Resistant or Refractory to Anti-EGFR TherapiesMol Cancer Ther. 2019 Jun;18(6):1104-1114. doi: 10.1158/1535-7163.MCT-18-0854. Epub 2019 Apr 8.
• Ref 52: A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancersOncotarget. 2016 Mar 8;7(10):10696-709. doi: 10.18632/oncotarget.7372.
• Ref 53: Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2Cancer Res. 2010 Jan 15;70(2):621-31. doi: 10.1158/0008-5472.CAN-09-2340. Epub 2010 Jan 12.
• Ref 54: Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastomaPLoS One. 2014 Apr 9;9(4):e94132. doi: 10.1371/journal.pone.0094132. eCollection 2014.
• Ref 55: Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast CancerN Engl J Med. 2019 May 16;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.
• Ref 56: PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitorsMol Cancer Ther. 2011 Mar;10(3):558-65. doi: 10.1158/1535-7163.MCT-10-0994. Epub 2011 Jan 7.
• Ref 57: PI3K inhibitor provides durable response in metastatic metaplastic carcinoma of the breast: A hidden gem in the BELLE-4 studyJ Formos Med Assoc. 2019 Sep;118(9):1333-1338. doi: 10.1016/j.jfma.2018.12.004. Epub 2018 Dec 18.
• Ref 58: Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation studyEur J Cancer. 2017 Sep;83:194-202. doi: 10.1016/j.ejca.2017.06.036. Epub 2017 Jul 24.
• Ref 59: HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8(6):215. doi: 10.1186/bcr1612.
• Ref 60: The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016 May 10;7:11479. doi: 10.1038/ncomms11479.
• Ref 61: Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancerOncogenesis. 2013 Dec 23;2(12):e83. doi: 10.1038/oncsis.2013.46.
• Ref 62: Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitorClin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15.
• Ref 63: MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell CarcinomaClin Cancer Res. 2015 Sep 1;21(17):3946-56. doi: 10.1158/1078-0432.CCR-14-3377. Epub 2015 May 14.