Molecule Information

General Information of the Molecule (ID: Mol00137)

• Name: Platelet-derived growth factor receptor alpha (PDGFRA) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: PDGFRA
• Gene ID: 5156
• Location: chr4:54229280-54298245[+]
• Sequence:
  MGTSHPAFLVLGCLLTGLSLILCQLSLPSILPNENEKVVQLNSSFSLRCFGESEVSWQYP
  MSEEESSDVEIRNEENNSGLFVTVLEVSSASAAHTGLYTCYYNHTQTEENELEGRHIYIY
  VPDPDVAFVPLGMTDYLVIVEDDDSAIIPCRTTDPETPVTLHNSEGVVPASYDSRQGFNG
  TFTVGPYICEATVKGKKFQTIPFNVYALKATSELDLEMEALKTVYKSGETIVVTCAVFNN
  EVVDLQWTYPGEVKGKGITMLEEIKVPSIKLVYTLTVPEATVKDSGDYECAARQATREVK
  EMKKVTISVHEKGFIEIKPTFSQLEAVNLHEVKHFVVEVRAYPPPRISWLKNNLTLIENL
  TEITTDVEKIQEIRYRSKLKLIRAKEEDSGHYTIVAQNEDAVKSYTFELLTQVPSSILDL
  VDDHHGSTGGQTVRCTAEGTPLPDIEWMICKDIKKCNNETSWTILANNVSNIITEIHSRD
  RSTVEGRVTFAKVEETIAVRCLAKNLLGAENRELKLVAPTLRSELTVAAAVLVLLVIVII
  SLIVLVVIWKQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRVLG
  SGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMSELKIMTHLGPHLNIVNL
  LGACTKSGPIYIITEYCFYGDLVNYLHKNRDSFLSHHPEKPKKELDIFGLNPADESTRSY
  VILSFENNGDYMDMKQADTTQYVPMLERKEVSKYSDIQRSLYDRPASYKKKSMLDSEVKN
  LLSDDNSEGLTLLDLLSFTYQVARGMEFLASKNCVHRDLAARNVLLAQGKIVKICDFGLA
  RDIMHDSNYVSKGSTFLPVKWMAPESIFDNLYTTLSDVWSYGILLWEIFSLGGTPYPGMM
  VDSTFYNKIKSGYRMAKPDHATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQYKK
  SYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDKLKDWEGGLDEQRLSADSGYII
  PLPDIDPVPEEEDLGKRNRHSSQTSEESAIETGSSSSTFIKREDETIEDIDMMDDIGIDS
  SDLVEDSFL
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.
• Uniprot ID: PGFRA_HUMAN
• Ensembl ID: ENSG00000134853
• HGNC ID: HGNC:8803

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) 9 drug(s) in total

Avapritinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Gastrointestinal stromal tumor [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.V658A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: Trsh1 cells; Stomach; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance.

Disease Class: Gastrointestinal stromal tumor [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.N659K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: Trsh1 cells; Stomach; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance.

Disease Class: Gastrointestinal stromal tumor [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.Y676C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: Trsh1 cells; Stomach; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance.

Disease Class: Gastrointestinal stromal tumor [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.G680R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: Trsh1 cells; Stomach; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [2]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: M-07e cells; Peripheral blood; Homo sapiens (Human); CVCL_2106
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: Chinese hamster ovary (CHO)-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Enzyme-linked immunosorbent assay; Cellular proliferation test assay

Disease Class: Gastrointestinal stromal tumor [2]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: M-07e cells; Peripheral blood; Homo sapiens (Human); CVCL_2106
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: Chinese hamster ovary (CHO)-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Enzyme-linked immunosorbent assay; Cellular proliferation test assay

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastrointestinal stromal cancer [3]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.D842_D846>G
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/STAT3 signaling pathway; Activation; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Radiological response evaluation assay; Pathological response evaluation assay
• Mechanism Description: The most common PDGFRA mutation, a D842_D846delinsG shows primary resistance to imatinib in the patients.

Disease Class: Gastrointestinal stromal cancer [3]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.I843_S847>T
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/STAT3 signaling pathway; Activation; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Radiological response evaluation assay; Pathological response evaluation assay
• Mechanism Description: The most common PDGFRA mutation, a D842V substitution in exon 18, shows primary resistance to imatinib in in vitro and in vivo studies.

Disease Class: Gastrointestinal stromal cancer [4], [5], [6]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.D842V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/STAT3 signaling pathway; Activation; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Radiological response evaluation assay; Pathological response evaluation assay
• Mechanism Description: The most common PDGFRA mutation, a I843_S847delinsT shows primary resistance to imatinib in the patients.

Midostaurin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [7]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Regorafenib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Gastrointestinal stromal tumor [8]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Regorafenib
• Molecule Alteration: IF-deletion; p.C814_S854 (c.2440_2562)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Gastrointestinal stromal tumor [9]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Regorafenib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gastrointestinal tract; .
• Experiment for Drug Resistance: CT scan assay; MRI assay

Disease Class: Gastrointestinal stromal tumor [8]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Regorafenib
• Molecule Alteration: Missense mutation; p.Y894C
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Gastrointestinal stromal tumor [8]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Regorafenib
• Molecule Alteration: IF-deletion; p.K552_G596 (c.1654_1788)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Gastrointestinal stromal tumor [8]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Regorafenib
• Molecule Alteration: IF-deletion; p.P631_G668 (c.1891_2004)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Gastrointestinal stromal tumor [8]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Regorafenib
• Molecule Alteration: Missense mutation; p.R748G (c.2242A>G)
• Experimental Note: Identified from the Human Clinical Data

Ripretinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [7]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ripretinib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Renal cell carcinoma [10]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance.

Disease Class: Gastrointestinal stromal cancer [11]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Resistant Drug: Sunitinib
• Molecule Alteration: Missense mutation; p.D842V
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: We were able to identify primary kIT mutations in all plasma samples. Additional mutations, including kIT exon 17 S821F and PDGFRA exon 18 D842V, were detected in the patient-matched plasma samples during follow-up and appeared to result in decreased sensitivity to TkIs. Our results demonstrate an approach by which primary and secondary mutations are readily detected in blood-derived circulating tumor DNA from patients with GIST.

Tamoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [12]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Missense mutation; p.D714E
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• 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: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.Y288C (c.863A>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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay
• Mechanism Description: PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib, consistent with pathway activation results.

Trastuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [12]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.D714E
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• 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.

Clinical Trial Drug(s) 2 drug(s) in total

Crenolanib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [13]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.Y288C (c.863A>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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay
• Mechanism Description: PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib, consistent with pathway activation results.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Gastrointestinal stromal tumor [14]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Complex-indel; p.D842_I843delinsVM (c.2524_2529delinsGTAATG)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Biochemical assessment of PDGFRA/KIT kinase activity assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The complex-indel p.D842_I843delinsVM (c.2524_2529delinsGTAATG) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target.

Disease Class: Gastrointestinal stromal tumor [14]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: IF-deletion; p.I843delI (c.2529_2531delCAT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Biochemical assessment of PDGFRA/KIT kinase activity assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The if-deletion p.I843delI (c.2529_2531delCAT) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target.

Disease Class: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay

Disease Class: Gastrointestinal stromal tumor [15]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.V561D (c.1682T>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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay

Disease Class: Solid tumour/cancer [16]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.P577S (c.1729C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [16]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.V658A (c.1973T>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [16]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.R841K (c.2522G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [16]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D842Y (c.2524G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.D842Y (c.2524G>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [16]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.H845Y (c.2533C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [16]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.G853D (c.2558G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.P577S (c.1729C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.V658A (c.1973T>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.R841K (c.2522G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.H845Y (c.2533C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.G853D (c.2558G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.P577S (c.1729C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.V658A (c.1973T>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.R841K (c.2522G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.H845Y (c.2533C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Melanoma [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.G853D (c.2558G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [14]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.N659K (c.1977C>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Biochemical assessment of PDGFRA/KIT kinase activity assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.N659K (c.1977C>G) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Gastrointestinal stromal tumor [14]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D842Y (c.2524G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Biochemical assessment of PDGFRA/KIT kinase activity assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.D842Y (c.2524G>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Disease Class: Gastrointestinal stromal tumor [14]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D842I (c.2524_2525delGAinsAT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Biochemical assessment of PDGFRA/KIT kinase activity assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.D842I (c.2524_2525delGAinsAT) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Omipalisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Omipalisib
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay
• Mechanism Description: PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib, consistent with pathway activation results.

Disease Class: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Omipalisib
• Molecule Alteration: Missense mutation; p.Y288C (c.863A>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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay
• Mechanism Description: PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib and trametinib, consistent with pathway activation results.

Disease Class: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Omipalisib
• Molecule Alteration: Missense mutation; p.V561D (c.1682T>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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Presto blue assay

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

Tamoxifen/Trastuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [12]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Tamoxifen/Trastuzumab
• Molecule Alteration: Missense mutation; p.D714E
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ALK signaling pathway; Activation; hsa05200
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• 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.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

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: 1.96E-01; Fold-change: -2.00E-01; Z-score: -2.93E-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: 3.48E-63; Fold-change: -4.08E-01; Z-score: -1.52E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.14E-09; Fold-change: -3.72E-01; Z-score: -1.14E+00

Kidney cancer [ICD-11: 2C90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Kidney
• The Specified Disease: Kidney cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.48E-03; Fold-change: -3.79E-01; Z-score: -1.26E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.43E-03; Fold-change: -1.19E-01; Z-score: -6.22E-01

References

• Ref 1: Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain .Cancer Discov. 2021 Jan;11(1):108-125. doi: 10.1158/2159-8290.CD-20-0487. Epub 2020 Sep 24. 10.1158/2159-8290.CD-20-0487
• Ref 2: A precision therapy against cancers driven by KIT/PDGFRA mutationsSci Transl Med. 2017 Nov 1;9(414):eaao1690. doi: 10.1126/scitranslmed.aao1690.
• Ref 3: Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients. Eur J Cancer. 2017 May;76:76-83. doi: 10.1016/j.ejca.2017.02.007. Epub 2017 Mar 8.
• Ref 4: Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003 Sep;125(3):660-7. doi: 10.1016/s0016-5085(03)01046-1.
• Ref 5: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. doi: 10.1200/JCO.2003.04.190.
• Ref 6: Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005 Feb;128(2):270-9. doi: 10.1053/j.gastro.2004.11.020.
• Ref 7: Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA VariantsCancer Cell. 2019 May 13;35(5):738-751.e9. doi: 10.1016/j.ccell.2019.04.006.
• Ref 8: National Comprehensive Cancer Network.
• Ref 9: Regorafenib treatment for advanced, refractory gastrointestinal stromal tumor: a report of the UK managed access programClin Sarcoma Res. 2014 Dec 4;4:17. doi: 10.1186/2045-3329-4-17. eCollection 2014.
• Ref 10: Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma. PLoS One. 2014 Jan 24;9(1):e86263. doi: 10.1371/journal.pone.0086263. eCollection 2014.
• Ref 11: Detection of KIT and PDGFRA mutations in the plasma of patients with gastrointestinal stromal tumor. Target Oncol. 2015 Dec;10(4):597-601. doi: 10.1007/s11523-015-0361-1. Epub 2015 Mar 5.
• Ref 12: 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 13: Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapiesNat Commun. 2018 Nov 2;9(1):4583. doi: 10.1038/s41467-018-06949-w.
• Ref 14: Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumorsClin Cancer Res. 2012 Aug 15;18(16):4375-84. doi: 10.1158/1078-0432.CCR-12-0625. Epub 2012 Jun 27.
• Ref 15: Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations.
• Ref 16: Large-scale analysis of PDGFRA mutations in melanomas and evaluation of their sensitivity to tyrosine kinase inhibitors imatinib and crenolanibClin Cancer Res. 2013 Dec 15;19(24):6935-42. doi: 10.1158/1078-0432.CCR-13-1266. Epub 2013 Oct 16.