Disease Information

General Information of the Disease (ID: DIS00065)

• Name: Gastrointestinal cancer
• ICD: ICD-11: 2B5B

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Avapritinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.T670I (c.2009C>T)
• Resistant Drug: Avapritinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: M230 cells; Skin; Homo sapiens (Human); CVCL_D749
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V654A (c.1961T>C)
• Resistant Drug: Avapritinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: M230 cells; Skin; Homo sapiens (Human); CVCL_D749
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [2]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V658A
• Resistant Drug: Avapritinib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [2]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.N659K
• Resistant Drug: Avapritinib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [2]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.Y676C
• Resistant Drug: Avapritinib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [2]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.G680R
• Resistant Drug: Avapritinib
• 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)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V560D (c.1679T>A)
• Sensitive Drug: Avapritinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: M230 cells; Skin; Homo sapiens (Human); CVCL_D749
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [3]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Sensitive Drug: Avapritinib
• 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

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [3]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Complex-indel; p.W557_V559delinsF (c.1670_1675delGGAAGG)
• Sensitive Drug: Avapritinib
• 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

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [3]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D820V (c.2459A>T)
• Sensitive Drug: Avapritinib
• 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

Axitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V559D (c.1676T>A)
• Sensitive Drug: Axitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST-5R cells; Gastric; Homo sapiens (Human); CVCL_A9M9
• In Vitro Model: GIST-48B cells; Gastric; Homo sapiens (Human); CVCL_M441
• In Vivo Model: Female BALB/c-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole transcriptome shotgun sequencing assay
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.V560_Y578del19 (c.1679_1735del57)
• Sensitive Drug: Axitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST-5R cells; Gastric; Homo sapiens (Human); CVCL_A9M9
• In Vitro Model: GIST-48B cells; Gastric; Homo sapiens (Human); CVCL_M441
• In Vivo Model: Female BALB/c-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole transcriptome shotgun sequencing assay
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.K642E (c.1924A>G)
• Sensitive Drug: Axitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST-5R cells; Gastric; Homo sapiens (Human); CVCL_A9M9
• In Vitro Model: GIST-48B cells; Gastric; Homo sapiens (Human); CVCL_M441
• In Vivo Model: Female BALB/c-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole transcriptome shotgun sequencing assay
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Cabozantinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Duplication; p.A502_Y503 (c.1504_1509)
• Sensitive Drug: Cabozantinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clinical GIST specimens; .
• In Vivo Model: NMRI mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. Cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Complex-indel; p.K558_G565delinsR (c.1673_1693del21)
• Sensitive Drug: Cabozantinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clinical GIST specimens; .
• In Vivo Model: NMRI mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. Cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6], [7], [8]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D820Y
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: KIT and PDGFRA mutation analysis was performed in the primary tumors of 27 patients. Of these, 17 tumors (63%) had primary mutations in kIT exon 11, 4 (15%) had primary mutations in kIT exon 9 mutation, and 6 (22%) wild-type kIT. PDGFRA mutations were not detected in any tumor. After surgery following imatinib treatment, mutation analysis was performed on the responsive and progressive lesions of 17 patients. In addition to the original mutation, one of two patients with FP harbored secondary mutation in kIT exon 17 in the progressive lesion, whereas the second patient had only the original mutation in the progressive lesion. In the five GP patients evaluated, all except one harbored a synchronous secondary mutation in kIT exon 17 in progressive lesions. Surprisingly, one patient harbored a synchronous secondary mutation in kIT exon 17, showing that kIT mutations were present in two different codons of exon 17 in five different progressive lesions. Responsive lesions, however, possessed only their original mutations.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7], [8]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816E
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: KIT and PDGFRA mutation analysis was performed in the primary tumors of 27 patients. Of these, 17 tumors (63%) had primary mutations in kIT exon 11, 4 (15%) had primary mutations in kIT exon 9 mutation, and 6 (22%) wild-type kIT. PDGFRA mutations were not detected in any tumor. After surgery following imatinib treatment, mutation analysis was performed on the responsive and progressive lesions of 17 patients. In addition to the original mutation, one of two patients with FP harbored secondary mutation in kIT exon 17 in the progressive lesion, whereas the second patient had only the original mutation in the progressive lesion. In the five GP patients evaluated, all except one harbored a synchronous secondary mutation in kIT exon 17 in progressive lesions. Surprisingly, one patient harbored a synchronous secondary mutation in kIT exon 17, showing that kIT mutations were present in two different codons of exon 17 in five different progressive lesions. Responsive lesions, however, possessed only their original mutations.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7], [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.T670E
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing assay
• Experiment for Drug Resistance: Magnetic resonance tomograph assay; Computer-assisted tomography assay
• Mechanism Description: Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired kIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.S709F
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing assay
• Experiment for Drug Resistance: Magnetic resonance tomograph assay; Computer-assisted tomography assay
• Mechanism Description: Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired kIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [10]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816A
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: PFS and OS were longer for patients with secondary kIT exon 13 or 14 mutations (which involve the kIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the kIT activation loop). Biochemical profiling studies confirmed the clinical results. The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [10], [11], [12]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.A829P
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: PFS and OS were longer for patients with secondary kIT exon 13 or 14 mutations (which involve the kIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the kIT activation loop). Biochemical profiling studies confirmed the clinical results. The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [13]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816H
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: While tyrosine ki.se inhibitors have been previously utilized for kIT-altered malig.ncies, this patient's specific mutation (D816H) has been shown to be resistant to both imatinib and sunitinib.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.Y578C
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Frameshift mutation; p.V569_Y578del
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.N680K
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.K818_D820>N
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Frameshift mutation; p.D579del
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [14]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D820V
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Exome sequencing assay; Microarray transcription analysis
• Experiment for Drug Resistance: Overall survival assay
• Mechanism Description: Sanger sequencing revealed that R8 harbored kIT D820Y and R9 had kIT D820V as secondary kIT mutations.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [15]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.S821F
• Resistant Drug: Imatinib
• 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.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6], [7], [16]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.T670I
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: In situ Cell Death Detection assay
• Mechanism Description: We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of kIT protein expression. We demonstrate downregulation of kIT transcription as an underlying mechanism for bortezomib-mediated inhibition of kIT expression. Collectively, our results show that inhibition of the proteasome using bortezomib can effectively kill imatinib-sensitive and imatinib-resistant GIST cells in vitro and provide a rationale to test the efficacy of bortezomib in GIST patients. Bortezomib has a dual mode of action against GIST cells involving upregulation of pro-apoptotic histone H2AX and downregulation of oncogenic kIT.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6], [7], [16]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.V654A
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6], [7], [17]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.Y823D
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9], [11], [17]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.N822Y
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6], [7], [16]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.N822K
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7], [8], [17]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D820G
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [17], [10]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D820A
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11], [17], [18]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816H
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8], [17], [18]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.C809G
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7], [16], [17]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D820E
• Resistant Drug: Imatinib
• 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
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [16]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816G
• Resistant Drug: Imatinib
• 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
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [16]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D716N
• Resistant Drug: Imatinib
• 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
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [16]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D820Y
• Resistant Drug: Imatinib
• 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
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [19]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Dimerisation; Up-regulation
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5 GIST tissues; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: These results demonstrated that the c-kit mutation drove auto-dimerisation, and promoted receptor phosphorylation, and ligand-independent receptor signalling pathway. Therefore, dimerisation is the common step in both the activation processes of KIT prior to phosphorylation and therefore, blocking receptor dimerisation may be more effective than blocking the phosphorylated receptor.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CCDC26 long non-coding RNA (CCDC26) [20]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Imatinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of LncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Key Molecule: CCDC26 long non-coding RNA (CCDC26) [21]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Imatinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: CCDC26 knockdown enhanced imatinib resistance in GIST cells and c-kIT knockdown reversed the imatinib resistance mediated by CCDC26 inhibition.

Key Molecule: hsa-miR-125a-5p [22]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous kIT mutation but not in GIST48 cells with double kIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, kIT mutational status and survival.

Key Molecule: hsa-mir-320 [23]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320a was downregulated in imatinib-resistant GISTs and low expression of miR-320a was found to be associated with short TTR. This confirmed that miR-320a was involved in the process of imatinib resistance.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [24], [9]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.K642E
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Secondary kIT mutations were identified in 11/14 (78.6%) imatinib-acquired-resistance patients, with nine patients in kIT gene exon17, and the other two in exon 13. The expressions of p-kIT, p-AkT, PCNA and BCL-2 were higher in the samples of imatinib-resistant GISTs than those of imatinib-responsive ones. P-kIT, p-AkT expressions were higher in imatinib acquired-resistance GISTs with secondary kIT mutations than imatinib-responsive ones with primary mutation. Total kIT, MAPk, p-MAPk, p-MTOR expressions were comparable in all varied GISTs.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [20]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Imatinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of LncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [21]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Imatinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: CCDC26 knockdown enhanced imatinib resistance in GIST cells and c-kIT knockdown reversed the imatinib resistance mediated by CCDC26 inhibition.

Key Molecule: Tyrosine-protein phosphatase non-receptor type 18 (PTPN18) [22]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous kIT mutation but not in GIST48 cells with double kIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, kIT mutational status and survival.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [25]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.V600E
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/RAF/Mek/ERK signaling pathway; Activation; hsa04010
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: High-performance liquid chromatography screening assay
• Mechanism Description: This finding, in combination with the loss of kIT expression, suggests the possibility of activation of RAS-RAF-MEk-ERk pathways driven by a kIT-independent oncogenic mechanism. Most mutations lie within the kinase domain with a single nucleotide substitution at position 1799 in exon 15, leading to the V600E amino-acid substitution (98 %).

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [26]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D842_D846>G
• Resistant Drug: Imatinib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [26]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.I843_S847>T
• Resistant Drug: Imatinib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [16], [27], [28]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D842V
• Resistant Drug: Imatinib
• 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [29]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Imatinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis Detection assay
• Mechanism Description: miRNA-21 sensitizes gastrointesti.l stromal tumors (GISTs) cells to Imatinib via targeting B-cell lymphoma 2 (Bcl-2), miRNA-21 suppressed Bcl-2 expression in GIST cells and could function as a potent tumor suppressor in GIST.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [29]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Imatinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis Detection assay
• Mechanism Description: miRNA-21 sensitizes gastrointesti.l stromal tumors (GISTs) cells to Imatinib via targeting B-cell lymphoma 2 (Bcl-2), miRNA-21 suppressed Bcl-2 expression in GIST cells and could function as a potent tumor suppressor in GIST.

Nilotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [30]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.N655T
• Resistant Drug: Nilotinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene mutation analysis assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: According to gene mutation analysis, the resistant GIST contained not only the primary genetic kIT mutation in not only exon 11 but also secondary kIT mutation in exon 13 (Asn655Thr).

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [31]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Other; .
• Resistant Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Metastatic GI stromal tumor tissue; .
• Mechanism Description: The mutation in gene BRAF cause the resistance of Regorafenib by unusual activation of pro-survival pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [32]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.T670I (c.2009C>T)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [33]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V560G (c.1679T>G)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.C788_N828 (c.2362_2484)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.R449_E514 (c.1345_1542)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.K550_G592 (c.1648_1776)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.P627_G664 (c.1879_1992)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.G664_C714 (c.1990_2142)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [35]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.K550_G592 (c.1648_1774)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [32]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V654A (c.1961T>C)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [33]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.K558_V559delKV (c.1672_1677delAAGGTT)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [33]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Complex-indel; p.K558delinsNP (c.1674delinsTCCT)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [33]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V559D (c.1676T>A)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [33]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.V560_L576del17 (c.1678_1728del51)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [33]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V560D (c.1679T>A)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [31]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D820Y (c.2458G>T)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Metastatic GI stromal tumor tissue; .
• Mechanism Description: The missense mutation p.D820Y (c.2458G>T) in gene KIT cause the sensitivity of Regorafenib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [36]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [37]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [36]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [36]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [36]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [36]

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

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [38]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Duplication; p.A502_Y503 (c.1504_1509)
• Sensitive Drug: Regorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: NOD/SCID mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Drug sensitivity test assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [39]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.K642E (c.1924A>G)
• Sensitive Drug: Regorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HUVEC cells; Endothelium; Homo sapiens (Human); N.A.
• In Vitro Model: HAoSMC cells; N.A.; .; N.A.
• In Vivo Model: Female athymic NCr nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTitre-Glo assay
• Mechanism Description: The missense mutation p.K642E (c.1924A>G) in gene KIT cause the sensitivity of Regorafenib by unusual activation of pro-survival pathway

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [40]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.N822K
• Resistant Drug: Sunitinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: The sunitinib-resistant liver and peritoneal tumors had different point mutations: T to G and T to A, respectively, although both resulted in an N822k amino acid alteration, indicating the polyclonal evolution of recurrent GISTs.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [13]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816H
• Resistant Drug: Sunitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: While tyrosine ki.se inhibitors have been previously utilized for kIT-altered malig.ncies, this patient's specific mutation (D816H) has been shown to be resistant to both imatinib and sunitinib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [15]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D842V
• Resistant Drug: Sunitinib
• 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.

Clinical Trial Drug(s) 1 drug(s) in total

Crenolanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [41]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Complex-indel; p.D842_I843delinsVM (c.2524_2529delinsGTAATG)
• Sensitive Drug: Crenolanib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [41]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.I843delI (c.2529_2531delCAT)
• Sensitive Drug: Crenolanib
• 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.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [42]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [41]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D842Y (c.2524G>T)
• Sensitive Drug: Crenolanib
• 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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [41]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D842I (c.2524_2525delGAinsAT)
• Sensitive Drug: Crenolanib
• 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

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

G007-LK/Imatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [43]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.V560delV (c.1679_1681delTTG)
• Sensitive Drug: G007-LK/Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: S2 GIST cells; N.A.; Mus musculus (Mouse); N.A.
• In Vitro Model: GIST T1 cells; Pleural effusion; Homo sapiens (Human); CVCL_4976
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Immunohistochemistry assay; Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Activation of the canonical Wnt pathway and accumulation of nuclear active beta-catenin were present in a subset of human GISTs that were treatment na ve, responsive to imatinib, or resistant to imatinib. The mechanism involved reduction of DKK4 and enhanced the nuclear beta-catenin stability by COP1 loss. Inhibiting Wnt/beta-catenin signaling alone or in combination with imatinib demonstrated anti-tumor efficacy in multiple cells and pre-clinical models in GIST.

Infigratinib/Imatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [44]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.V560_Y578del19 (c.1679_1735del57)
• Sensitive Drug: Infigratinib/Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vivo Model: Athymic (nu/nu) female GIST882 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony formation assay; Real-time cell proliferation assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [44]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.K642E (c.1924A>G)
• Sensitive Drug: Infigratinib/Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vivo Model: Athymic (nu/nu) female GIST882 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony formation assay; Real-time cell proliferation assay

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