Molecule Information

General Information of the Molecule (ID: Mol04082)

• Name: AKT serine/threonine kinase (AKT) ,Homo sapiens
• Synonyms: Protein kinase B; Protein kinase B alpha; Proto-oncogene c-Akt; RAC-PK-alpha
• Molecule Type: Protein
• Gene Name: AKT1
• Gene ID: 207
• Location: chr14:104769349-104795759[-]
• Sequence:
  MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
  QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF
  RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI
  LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS
  RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI
  KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL
  ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK
  LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
• Function: AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:11882383, PubMed:15526160, PubMed:15861136, PubMed:21432781, PubMed:21620960, PubMed:31204173). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:11882383, PubMed:15526160, PubMed:21432781, PubMed:21620960, PubMed:31204173). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:11882383, PubMed:15526160, PubMed:21432781, PubMed:21620960). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the mTORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915, PubMed:12172553). Also regulates the mTORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 and DEPDC5 (PubMed:31548394, PubMed:33594058). AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Part of a positive feedback loop of mTORC2 signaling by mediating phosphorylation of MAPKAP1/SIN1, promoting mTORC2 activation (By similarity). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3- 3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser- 319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor 1 (IGF1) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF1 (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865). Acts as a regulator of mitochondrial calcium uptake by mediating phosphorylation of MICU1 in the mitochondrial intermembrane space, impairing MICU1 maturation (PubMed:30504268). Acts as an inhibitor of tRNA methylation by mediating phosphorylation of the N-terminus of METTL1, thereby inhibiting METTL1 methyltransferase activity (PubMed:15861136). In response to LPAR1 receptor pathway activation, phosphorylates Rabin8/RAB3IP which alters its activity and phosphorylates WDR44 which induces WDR44 binding to Rab11, thereby switching Rab11 vesicular function from preciliary trafficking to endocytic recycling (PubMed:31204173). .
• Uniprot ID: AKT1_HUMAN
• Ensembl ID: ENSG00000142208
• HGNC ID: HGNC:391

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

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Dacomitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [3]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2] [4]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [5]

• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: MKN-45/R cells; Gastric; Homo sapiens (Human); N.A.
• In Vitro Model: MKN-74/R cells; Gastric; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [5]

• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: MKN-45/R cells; Gastric; Homo sapiens (Human); N.A.
• In Vitro Model: MKN-74/R cells; Gastric; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.

Flutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Prostate cancer [ICD-11: 2C82.0] [6]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Flutamide
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: LN-FLU cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The PI3K/Akt/mTOR pathway is involved in the regulation of cancer cell survival, proliferation, growth, and metabolism. In most prostate cancer cell lines, the PIP3 phosphatase PTEN, which antagonizes this pathway, is mutated and therefore the PI3K/Akt/mTOR pathway is activated. To examine the functioning of this pathway, we determined the expressions and phosphorylation levels of Akt and mTOR via Western blot. As shown in, in the drug-resistant LN-FLU cells, both the phosphorylation levels and overall expressions of Akt and mTOR were decreased when compared to the LNCaP cells. The results in the LN-FLU cells were similar to those observed in the androgen-resistant PC3 cells, which were used as a positive control. The decrease in Akt and mTOR signaling suggests a proliferative arrest of the drug-resistant LN-FLU cells.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic lymphocytic leukemia [ICD-11: 2A82.0] [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD5+19+ cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: MEC1 cells; Blood; Homo sapiens (Human); CVCL_1870
• In Vitro Model: HS-5 cells; Bone marrow; Homo sapiens (Human); CVCL_3720
• In Vivo Model: NSG mice model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Induction of transcription factor FoxO1 during ibrutinib therapy upregulates Rictor, an mTORC2 assembly protein, leading to phosphorylation of Akt, an essential molecule supporting CLL cell survival

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K+Akt signaling pathway; Activation; hsa04151
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; Immunofluorescence staining assay; Immunohistochemistry; RNA sequencing assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay; EdU incorporation assay; Cell apoptosis assay
• Mechanism Description: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients.

Pomalidomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Epstein-barr virus (ebv) infection [ICD-11: XN0R2] [8]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Sensitive Drug: Pomalidomide
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Clinical Trial Drug(s) 4 drug(s) in total

Dactolisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2] [4]

• Sensitive Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Sensitive Drug: Dactolisib
• Molecule Alteration: Phosphorylation; T1080S
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [9]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Selumetinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Activation; hsa04151
• In Vitro Model: BRAF L525R cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in?BRAF?L525R cells but not in?BRAF?V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in?BRAF?L525R cells but not in?BRAF?V600E cells or selumetinib-resistant?BRAF?L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.

Vemurafenib/Cobimetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [10]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: Hs294T R cells; Skin; Homo sapiens (Human); CVCL_E3AI
• In Vitro Model: WM9 R cells; melanoma; Homo sapiens (Human); CVCL_E3AH
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time.

Endoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6] [11]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6]
• Resistant Drug: Endoxifen
• Molecule Alteration: Autophosphorylation; S473
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ER+ MCF7 BC cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: TRC cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Therefore, our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells. Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

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

BEZ235/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [9]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: BEZ235/Ruxolitinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Activation; hsa04151
• In Vitro Model: BRAF L525R cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in?BRAF?L525R cells but not in?BRAF?V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in?BRAF?L525R cells but not in?BRAF?V600E cells or selumetinib-resistant?BRAF?L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.

References

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• Ref 2: Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2. Mol Oncol. 2025 Feb;19(2):377-390.
• Ref 3: Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells. Molecules. 2024 Jan 4;29(1):274.
• Ref 4: [Reversal Effect of NVP-BEZ235 on Doxorubicin-Resistance in Burkitt Lymphoma RAJI Cell Line]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2024 Apr;32(2):476-482.
• Ref 5: Inhibition of PI3K/Akt/mTOR Signaling Pathway Suppresses 5-Fluorouracil Resistance in Gastric Cancer. Mol Biotechnol. 2024 Dec;66(12):3640-3654.
• Ref 6: Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications. Int J Mol Sci. 2023 Oct 26;24(21):15626.
• Ref 7: FoxO1/Rictor axis induces a nongenetic adaptation to ibrutinib via Akt activation in chronic lymphocytic leukemia. J Clin Invest. 2024 Oct 22;134(23):e173770.
• Ref 8: Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas. Sci Rep. 2023 Jul 18;13(1):11596.
• Ref 9: Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant. Int J Clin Oncol. 2023 May;28(5):654-663.
• Ref 10: Characterization of two melanoma cell lines resistant to BRAF/MEK inhibitors (vemurafenib and cobimetinib). Cell Commun Signal. 2024 Aug 23;22(1):410.
• Ref 11: Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells. J Mol Cell Biol. 2021 Sep 11;13(6):433-444.