Molecule Information

General Information of the Molecule (ID: Mol00635)

• Name: Smoothened homolog (SMO) ,Homo sapiens
• Synonyms: SMO; Protein Gx; SMOH
• Molecule Type: Protein
• Gene Name: SMO
• Gene ID: 6608
• Location: chr7:129188633-129213545[+]
• Sequence:
  MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPP
  LSHCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWA
  VIQPLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTN
  EVQNIKFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAV
  TGLCTLFTLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGT
  MRLGEPTSNETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYF
  HLLTWSLPFVLTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLI
  RGVMTLFSIKSNHPGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEW
  ERSFRDYVLCQANVTIGLPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVWTKA
  TLLIWRRTWCRLTGQSDDEPKRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPV
  AGLAFDLNEPSADVSSAWAQHVTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAE
  ISPELQKRLGRKKKRRKRKKEVCPLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWG
  AGDSCRQGAWTLVSNPFCPEPSPPQDPFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTEL
  MDADSDF
• Function: G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation.
• Uniprot ID: SMO_HUMAN
• Ensembl ID: ENSG00000128602
• HGNC ID: HGNC:11119

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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 6 drug(s) in total

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [1]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [1]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Oxaliplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [1]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Oxaliplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Sonidegib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Basal cell carcinoma [2]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.D473H (c.1417G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Drug Resistance: Efficacy analysis

Disease Class: Basal cell carcinoma [2]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.D473G (c.1418A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Drug Resistance: Efficacy analysis

Disease Class: Basal cell carcinoma [2]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.S533N (c.1598G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Drug Resistance: Efficacy analysis

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.I408V (c.1222A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.I408V (c.1222A>G) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.A459V (c.1376C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.A459V (c.1376C>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.C469Y (c.1406G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.C469Y (c.1406G>A) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.T241M (c.722C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.T241M (c.722C>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.W281C (c.843G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.W281C (c.843G>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.V321M (c.961G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.V321M (c.961G>A) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.D384N (c.1150G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Disease Class: Solid tumour/cancer [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.S387N (c.1160G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Disease Class: Solid tumour/cancer [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.E518K (c.1552G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Disease Class: Solid tumour/cancer [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.N219D (c.655A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Basal cell carcinoma [2]

• Sensitive Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Sensitive Drug: Sonidegib
• Molecule Alteration: Missense mutation; p.W535L (c.1604G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Drug Resistance: Efficacy analysis

Vismodegib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.W535R
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.W535L
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.W281C
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.V321A
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.S533N
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.Q477E
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.H231R
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.F460L
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.D473N
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.D473H
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [5]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.D473G
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Disease Class: Basal cell carcinoma [3]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.V321M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Disease Class: Basal cell carcinoma [3]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.T241M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Disease Class: Basal cell carcinoma [3]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.C469Y
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Disease Class: Basal cell carcinoma [3]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.A459V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• In Vitro Model: Human skin tissue; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Disease Class: Basal cell carcinoma [6]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.G497W
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.

Disease Class: Basal cell carcinoma [6]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.D473Y
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.

Disease Class: Basal cell carcinoma [7]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.W281L
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Magnetic resonance imaging assay
• Mechanism Description: Upregulation of Hedgehog (Hh) signaling is crucial in the development of almost all BCCs. Vismodegib resistance in medulloblastoma is caused by acquired mutations in SMO.

Disease Class: Basal cell carcinoma [7]

• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Resistant Drug: Vismodegib
• Molecule Alteration: Missense mutation; p.V321M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Magnetic resonance imaging assay
• Mechanism Description: Upregulation of Hedgehog (Hh) signaling is crucial in the development of almost all BCCs. Vismodegib resistance in medulloblastoma is caused by acquired mutations in SMO.

Curcumin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma [8]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Curcumin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Inhibition; hsa05217
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR326 exerts a tumor inhibition effect by decreasing the activity of the SHH/GLI1 pathway. miR326 could target the SMO oncogene to inhibit the biological behaviors and stemness of glioma cells.

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

Patidegib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Medulloblastoma [9]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Sensitive Drug: Patidegib
• Molecule Alteration: Missense mutation; p.D473H (c.1417G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Bone marrow; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.D473H (c.1417G>C) in gene SMO cause the sensitivity of Patidegib by unusual activation of pro-survival pathway

Taladegib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Taladegib
• Molecule Alteration: Missense mutation; p.I408V (c.1222A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.I408V (c.1222A>G) in gene SMO cause the resistance of Taladegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Taladegib
• Molecule Alteration: Missense mutation; p.A459V (c.1376C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.A459V (c.1376C>T) in gene SMO cause the resistance of Taladegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Taladegib
• Molecule Alteration: Missense mutation; p.C469Y (c.1406G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.C469Y (c.1406G>A) in gene SMO cause the resistance of Taladegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Taladegib
• Molecule Alteration: Missense mutation; p.T241M (c.722C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.T241M (c.722C>T) in gene SMO cause the resistance of Taladegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Taladegib
• Molecule Alteration: Missense mutation; p.W281C (c.843G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.W281C (c.843G>T) in gene SMO cause the resistance of Taladegib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Taladegib
• Molecule Alteration: Missense mutation; p.V321M (c.961G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.V321M (c.961G>A) in gene SMO cause the resistance of Taladegib by aberration of the drug's therapeutic target

JQ1

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: JQ1
• Molecule Alteration: Missense mutation; p.A459V (c.1376C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.A459V (c.1376C>T) in gene SMO cause the sensitivity of JQ1 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: JQ1
• Molecule Alteration: Missense mutation; p.C469Y (c.1406G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.C469Y (c.1406G>A) in gene SMO cause the sensitivity of JQ1 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: JQ1
• Molecule Alteration: Missense mutation; p.T241M (c.722C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.T241M (c.722C>T) in gene SMO cause the sensitivity of JQ1 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: JQ1
• Molecule Alteration: Missense mutation; p.W281C (c.843G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.W281C (c.843G>T) in gene SMO cause the sensitivity of JQ1 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: JQ1
• Molecule Alteration: Missense mutation; p.V321M (c.961G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.V321M (c.961G>A) in gene SMO cause the sensitivity of JQ1 by aberration of the drug's therapeutic target

TAK-441

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [10]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAK-441
• Molecule Alteration: Missense mutation; p.D473H (c.1417G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: [3H]-TAK-441 radioligand membrane binding assay; Affinity selection-MS binding assay

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

MRT-92

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.V329F (c.985_987delGTGinsTTT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.D384A (c.1151A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.Y394A (c.1180_1181delTAinsGC)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.T466F (c.1396_1397delACinsTT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.E518K (c.1552G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.M525G (c.1573_1574delATinsGG)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Disease Class: Solid tumour/cancer [11]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: MRT-92
• Molecule Alteration: Missense mutation; p.L325F (c.973_975delCTGinsTTT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [11]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: MRT-92
• Molecule Alteration: Missense mutation; p.R400A (c.1198_1199delCGinsGC)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; [3H]-TAK-441 radioligand membrane binding assay

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

GDP-beta-L-galactose

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Medulloblastoma [12]

• Resistant Disease: Medulloblastoma [ICD-11: 2A00.10]
• Resistant Drug: GDP-beta-L-galactose
• Molecule Alteration: Missense mutation; p.D473H
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Deep sequencing assay
• Experiment for Drug Resistance: Fluorescence-activated cell sorting (FACS) analysis
• Mechanism Description: Molecular profiling of the medulloblastoma patient's primary and metastatic tumor taken before treatment with GDC-0449 revealed an underlying somatic mutation in PTCH1 (PTCH1-W844C) as well as up-regulated expression of Hh pathway target genes, supporting the hypothesis that the tumor was driven by dysregulated Hh signaling. SMO-D473H transfection induced Hh pathway activity to levels comparable with that seen with SMO-WT, demonstrating that SMO-D473H is fully capable of activating Hh signaling.

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: 1.24E-33; Fold-change: 2.81E-01; Z-score: 7.35E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.04E-03; Fold-change: 5.79E-01; Z-score: 6.79E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.43E-02; Fold-change: 1.80E-01; Z-score: 7.11E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.31E-03; Fold-change: -6.99E-01; Z-score: -1.58E+00

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: 3.86E-01; Fold-change: -2.73E-01; Z-score: -3.77E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.26E-01; Fold-change: 2.59E-02; Z-score: 8.56E-02

References

• Ref 1: MiR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened. Int J Clin Exp Pathol. 2015 Jun 1;8(6):6397-406. eCollection 2015.
• Ref 2: An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to VismodegibClin Cancer Res. 2016 Mar 15;22(6):1325-9. doi: 10.1158/1078-0432.CCR-15-1588. Epub 2015 Nov 6.
• Ref 3: Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 2015 Mar 9;27(3):327-41. doi: 10.1016/j.ccell.2015.02.001.
• Ref 4: Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell CarcinomaMol Cancer Ther. 2016 May;15(5):866-76. doi: 10.1158/1535-7163.MCT-15-0729-T. Epub 2016 Jan 28.
• Ref 5: Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell. 2015 Mar 9;27(3):342-53. doi: 10.1016/j.ccell.2015.02.002.
• Ref 6: Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Mol Oncol. 2015 Feb;9(2):389-97. doi: 10.1016/j.molonc.2014.09.003. Epub 2014 Sep 26.
• Ref 7: Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014 Nov;71(5):1005-8. doi: 10.1016/j.jaad.2014.08.001. Epub 2014 Sep 4.
• Ref 8: MicroRNA-326 sensitizes human glioblastoma cells to curcumin via the SHH/GLI1 signaling pathway. Cancer Biol Ther. 2018 Apr 3;19(4):260-270. doi: 10.1080/15384047.2016.1250981. Epub 2018 Feb 22.
• Ref 9: Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma modelProc Natl Acad Sci U S A. 2012 May 15;109(20):7859-64. doi: 10.1073/pnas.1114718109. Epub 2012 May 1.
• Ref 10: Inhibition mechanism exploration of investigational drug TAK-441 as inhibitor against Vismodegib-resistant Smoothened mutantEur J Pharmacol. 2014 Jan 15;723:305-13. doi: 10.1016/j.ejphar.2013.11.014. Epub 2013 Nov 28.
• Ref 11: MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptorFASEB J. 2015 May;29(5):1817-29. doi: 10.1096/fj.14-267849. Epub 2015 Jan 30.
• Ref 12: Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009 Oct 23;326(5952):572-4. doi: 10.1126/science.1179386. Epub 2009 Sep 2.