Drug Information
Drug (ID: DG00050) and It's Reported Resistant Information
Name |
Crizotinib
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Synonyms |
Xalkori (TN); novel ALK inhibitors
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Indication |
In total 1 Indication(s)
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Structure | |||||
Drug Resistance Disease(s) |
Disease(s) with Clinically Reported Resistance for This Drug
(2 diseases)
Brain cancer [ICD-11: 2A00]
[2]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug
(1 diseases)
Lung cancer [ICD-11: 2C25]
[1]
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Target | ALK tyrosine kinase receptor (ALK) | ALK_HUMAN | [1] | ||
HGF/Met signaling pathway (HGF/Met pathway) | NOUNIPROTAC | [1] | |||
Proto-oncogene c-Met (MET) | MET_HUMAN | [1] | |||
Proto-oncogene c-Ros (ROS1) | ROS1_HUMAN | [1] | |||
Click to Show/Hide the Molecular Information and External Link(s) of This Drug | |||||
Formula |
C21H22Cl2FN5O
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IsoSMILES |
C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N
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InChI |
1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
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InChIKey |
KTEIFNKAUNYNJU-GFCCVEGCSA-N
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PubChem CID | |||||
ChEBI ID | |||||
TTD Drug ID | |||||
VARIDT ID | |||||
INTEDE ID | |||||
DrugBank ID |
Type(s) of Resistant Mechanism of This Drug
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 Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Brain cancer [ICD-11: 2A00]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Aberration of the Drug's Therapeutic Target (ADTT) | ||||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [6] | |||
Molecule Alteration | Missense mutation | p.F1174L |
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Resistant Disease | Neuroblastoma [ICD-11: 2A00.11] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | Cell invasion | Activation | hsa05200 | |
Cell migration | Activation | hsa04670 | ||
Cell proliferation | Activation | hsa05200 | ||
In Vitro Model | NBLW cells | Brain | Homo sapiens (Human) | CVCL_VJ90 |
NBLW-R cells | Brain | Homo sapiens (Human) | CVCL_VJ91 | |
Experiment for Molecule Alteration |
Sangersequencing assay; Targeted deep sequencing assay | |||
Experiment for Drug Resistance |
Array CGH assay | |||
Mechanism Description | Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells. | |||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [2] | |||
Molecule Alteration | Missense mutation | p.F1174L |
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Resistant Disease | Neuroblastoma [ICD-11: 2A00.11] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | ALK signaling pathway | Activation | hsa05200 | |
Cell apoptosis | Inhibition | hsa04210 | ||
Cell invasion | Activation | hsa05200 | ||
In Vitro Model | NCI-H3122 cells | Lung | Homo sapiens (Human) | CVCL_5160 |
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Direct sequencing assay | |||
Experiment for Drug Resistance |
MTS assay | |||
Mechanism Description | There is a C to G mutation (asterix) in codon 3522 in exon 23 resulting in the F1174L mutation. When present in cis with an ALk translocation, this mutation (also detected in neuroblastomas) causes an increase in ALk phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALk signaling and blocks apoptosis in RANBP2-ALk Ba/F3 cells. |
Lung cancer [ICD-11: 2C25]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Aberration of the Drug's Therapeutic Target (ADTT) | ||||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [7], [8], [9] | |||
Molecule Alteration | Missense mutation | p.S1206Y |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT/STAT signaling pathway | Activation | hsa04630 | |
In Vitro Model | ALCL cells | Lung | Homo sapiens (Human) | N.A. |
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Low throughout experiment assay; Next-generation sequencing assay | |||
Experiment for Drug Resistance |
X-ray tomography assay; Computerized tomography assay; Progression-free survival assay | |||
Mechanism Description | The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALk) gene rearrangements invariably develop resistance to the ALk tyrosine kinase inhibitor (TkI) crizotinib. In particular, ceritinib effectively inhibits ALk harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of ceritinib bound to ALk provides structural bases for this increased potency. Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [4], [7], [8] | |||
Molecule Alteration | Missense mutation | p.G1269A |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT/STAT signaling pathway | Activation | hsa04630 | |
In Vitro Model | ALCL cells | Lung | Homo sapiens (Human) | N.A. |
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Low throughout experiment assay; Pyrosequencing analysis; Droplet digital PCR assay; Next generation deep sequencing assay; Next-generation sequencing assay; Low throughput experiment assay | |||
Experiment for Drug Resistance |
X-ray tomography assay; Analysis of progression-free survival (PFS) assay; Computerized tomography assay; Progression-free survival assay | |||
Mechanism Description | The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. By applying a base-pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALk kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting. Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALk) gene rearrangements invariably develop resistance to the ALk tyrosine kinase inhibitor (TkI) crizotinib. In particular, ceritinib effectively inhibits ALk harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of ceritinib bound to ALk provides structural bases for this increased potency. Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [8], [9] | |||
Molecule Alteration | Missense mutation | p.G1202R |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT/STAT signaling pathway | Activation | hsa04630 | |
In Vitro Model | ALCL cells | Lung | Homo sapiens (Human) | N.A. |
Experiment for Molecule Alteration |
Low throughout experiment assay | |||
Experiment for Drug Resistance |
X-ray tomography assay | |||
Mechanism Description | The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [9] | |||
Molecule Alteration | Missense mutation | p.F1174C |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT/STAT signaling pathway | Activation | hsa04630 | |
In Vitro Model | ALCL cells | Lung | Homo sapiens (Human) | N.A. |
Experiment for Molecule Alteration |
Low throughout experiment assay | |||
Experiment for Drug Resistance |
X-ray tomography assay | |||
Mechanism Description | The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [9] | |||
Molecule Alteration | Missense mutation | p.I1171T |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT/STAT signaling pathway | Activation | hsa04630 | |
In Vitro Model | ALCL cells | Lung | Homo sapiens (Human) | N.A. |
Experiment for Molecule Alteration |
Low throughout experiment assay | |||
Experiment for Drug Resistance |
X-ray tomography assay | |||
Mechanism Description | The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [9] | |||
Molecule Alteration | Missense mutation | p.L1196M |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT/STAT signaling pathway | Activation | hsa04630 | |
In Vitro Model | ALCL cells | Lung | Homo sapiens (Human) | N.A. |
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Low throughout experiment assay | |||
Experiment for Drug Resistance |
X-ray tomography assay | |||
Mechanism Description | The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. By applying a base-pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALk kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting. Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. In contrast, cells expressing either the C1156Y or L1196M mutant form manifested a markedly reduced sensitivity to the drug. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [10], [11] | |||
Molecule Alteration | Missense mutation | p.L1196M |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | NCI-H2228 cells | Lung | Homo sapiens (Human) | CVCL_1543 |
NCI-H3122 cells | Lung | Homo sapiens (Human) | CVCL_5160 | |
SNU-2535 cells | Lung | Homo sapiens (Human) | CVCL_R756 | |
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Direct sequencing assay; Sanger dideoxynucleotide sequencing assay | |||
Experiment for Drug Resistance |
CCK8 assay; Flow cytometry assay; CellTiter-Glo assay | |||
Mechanism Description | Three patients harbored secondary ALk mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Genetic changes associated with crizotinib resistance are heterogeneous in ALk-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance. In 1 of the 15 cases examined, ALk FISH revealed high-level gene amplification. No ALk resistance mutations were found in this specimen, so it appears that high-level amplification of the wild-type ALk fusion gene is sufficient to cause resistance. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [11], [12] | |||
Molecule Alteration | Missense mutation | p.G1269A |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | NCI-H2228 cells | Lung | Homo sapiens (Human) | CVCL_1543 |
NCI-H3122 cells | Lung | Homo sapiens (Human) | CVCL_5160 | |
SNU-2535 cells | Lung | Homo sapiens (Human) | CVCL_R756 | |
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Direct sequencing assay; Digital droplet PCR assay; Sanger sequencing assay | |||
Experiment for Drug Resistance |
CCK8 assay; Flow cytometry assay; Progression-free survival (PFS) assay | |||
Mechanism Description | Three patients harbored secondary ALk mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Genetic changes associated with crizotinib resistance are heterogeneous in ALk-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance. ALk-dependent mechanisms include gatekeeper (L1196M) or other mutations such as C1156Y and G1269A in the ALk kinase domain and ALk copy number gain. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [10] | |||
Molecule Alteration | Missense mutation | p.T1151_L1152insT |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Sanger dideoxynucleotide sequencing assay | |||
Experiment for Drug Resistance |
CellTiter-Glo assay | |||
Mechanism Description | In 1 of the 15 cases examined, ALk FISH revealed high-level gene amplification. No ALk resistance mutations were found in this specimen, so it appears that high-level amplification of the wild-type ALk fusion gene is sufficient to cause resistance. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [10] | |||
Molecule Alteration | Missense mutation | p.S1206Y |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Sanger dideoxynucleotide sequencing assay | |||
Experiment for Drug Resistance |
CellTiter-Glo assay | |||
Mechanism Description | In 1 of the 15 cases examined, ALk FISH revealed high-level gene amplification. No ALk resistance mutations were found in this specimen, so it appears that high-level amplification of the wild-type ALk fusion gene is sufficient to cause resistance. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [10], [13] | |||
Molecule Alteration | Missense mutation | p.G1202R |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Sanger dideoxynucleotide sequencing assay; Next-generation sequencing assay | |||
Experiment for Drug Resistance |
CellTiter-Glo assay; Computerized tomography assay | |||
Mechanism Description | In 1 of the 15 cases examined, ALk FISH revealed high-level gene amplification. No ALk resistance mutations were found in this specimen, so it appears that high-level amplification of the wild-type ALk fusion gene is sufficient to cause resistance. Next-Generation Sequencing Reveals a Novel NSCLC ALk F1174V Mutation and Confirms ALk G1202R Mutation Confers High-Level Resistance to Alectinib (CH5424802/RO5424802) in ALk-Rearranged NSCLC Patients Who Progressed on Crizotinib. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [14] | |||
Molecule Alteration | Missense mutation | p.I1171T |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
RT-PCR assay; Direct sequencing assay | |||
Experiment for Drug Resistance |
Computerized tomography assay | |||
Mechanism Description | A rebiopsy of the pleural effusion showed a previously unidentified secondary mutation of the ALk gene at codon 1171 (I1171T). | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [8] | |||
Molecule Alteration | Mutation | 1151Tins |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Low throughput experiment assay | |||
Experiment for Drug Resistance |
Progression-free survival assay | |||
Mechanism Description | Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [12] | |||
Molecule Alteration | Missense mutation | p.C1156Y |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Digital droplet PCR assay; Sanger sequencing assay | |||
Experiment for Drug Resistance |
Analysis of progression-free survival (PFS) assay | |||
Mechanism Description | ALk-dependent mechanisms include gatekeeper (L1196M) or other mutations such as C1156Y and G1269A in the ALk kinase domain and ALk copy number gain. | |||
Key Molecule: Hepatocyte growth factor receptor (MET) | [15] | |||
Molecule Alteration | Missense mutation | p.D1228N |
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Resistant Disease | Lung squamous cell carcinoma [ICD-11: 2C25.3] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Snapshot next-generation sequencing assay | |||
Experiment for Drug Resistance |
Computed tomography assay | |||
Mechanism Description | An acquired mutation in the MET kinase domain, D1228N, was found at time of progression on crizotinib in a patient with MET exon 14 skipping. Crystal structures of type I MET inhibitors bound to the MET kinase domain show an important binding interaction with the Y1230 residue, with D1228 playing a role in stabilizing the conformation of the activation loop. Therefore, in addition to intrinsic transforming activity, disruption of the drug binding interaction between type I inhibitors and the MET kinase domain is hypothesized to underlie the mechanism of resistance of these specific mutations. | |||
Key Molecule: Hepatocyte growth factor receptor (MET) | [16] | |||
Molecule Alteration | Missense mutation | p.Y1230C |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Noninvasive plasma-based ctDNA assay | |||
Experiment for Drug Resistance |
Computed tomography assay | |||
Mechanism Description | Emergence of the preexisting MET Y1230C likely confers resistance to crizotinib in this case of METex14-positive NSCLC. Existence of pretreatment MET Y1230C may eventually modulate the response of METMET tyrosine kinase inhibitors. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [3], [4], [5] | |||
Molecule Alteration | Missense mutation | p.C1156Y |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vivo Model | A retrospective survey in conducting clinical studies | Homo sapiens | ||
Experiment for Molecule Alteration |
Liquid biopsy assay; Next-generation sequencing assay; Circulating-free DNA assay; Digital PCR assay; Pyrosequencing analysis; Droplet digital PCR assay; Next generation deep sequencing assay | |||
Experiment for Drug Resistance |
Analysis of progression-free survival (PFS) assay; Overall and disease-free assay | |||
Mechanism Description | In contrast, cells expressing either the C1156Y or L1196M mutant form manifested a markedly reduced sensitivity to the drug (23836314; 20979470). By applying a base-pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALk kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting. | |||
Key Molecule: Hepatocyte growth factor receptor (MET) | [17] | |||
Molecule Alteration | Missense mutation | p.D1246N |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Circulating tumour DNA (ctDNA) analysis; Next-generation sequencing assay | |||
Experiment for Drug Resistance |
Computed tomography assay | |||
Mechanism Description | MET exon 14 splicing mutation was identified in a Chinese patient in ctDNA. Three mutation in the MET kinase domain were related to resistance to crizotinib. | |||
Key Molecule: Hepatocyte growth factor receptor (MET) | [17] | |||
Molecule Alteration | Missense mutation | p.D1246H |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Circulating tumour DNA (ctDNA) analysis; Next-generation sequencing assay | |||
Experiment for Drug Resistance |
Computed tomography assay | |||
Mechanism Description | MET exon 14 splicing mutation was identified in a Chinese patient in ctDNA. Three mutation in the MET kinase domain were related to resistance to crizotinib. | |||
Key Molecule: Hepatocyte growth factor receptor (MET) | [17] | |||
Molecule Alteration | Missense mutation | p.Y1248H |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Circulating tumour DNA (ctDNA) analysis; Next-generation sequencing assay | |||
Experiment for Drug Resistance |
Computed tomography assay | |||
Mechanism Description | MET exon 14 splicing mutation was identified in a Chinese patient in ctDNA. Three mutation in the MET kinase domain were related to resistance to crizotinib. | |||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: hsa-miR-100-5p | [1] | |||
Molecule Alteration | Expression | Up-regulation |
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Resistant Disease | Eml4-alk positive non-small cell lung cancer [ICD-11: 2C25.8] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell proliferation | Activation | hsa05200 | |
mTOR signaling pathway | Inhibition | hsa04150 | ||
In Vitro Model | DFCI032 cells | Lung | Homo sapiens (Human) | CVCL_A763 |
NCI-H2228 cells | Lung | Homo sapiens (Human) | CVCL_1543 | |
Experiment for Molecule Alteration |
qRT-PCR | |||
Experiment for Drug Resistance |
Cell viability assay; Toxilight cytotoxicity assay | |||
Mechanism Description | miR-100-5p confers resistance to ALk tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALk positive NSCLC. | |||
Unusual Activation of Pro-survival Pathway (UAPP) | ||||
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) | [8] | |||
Molecule Alteration | Structural variation | Copy number gain |
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Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
Low throughput experiment assay | |||
Experiment for Drug Resistance |
Progression-free survival assay | |||
Mechanism Description | Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. | |||
Key Molecule: ALK tyrosine kinase receptor (ALK) | [18], [19] | |||
Molecule Alteration | Mutation | . |
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Resistant Disease | ALk-rearranged non-small cell lung cancer [ICD-11: 2C25.6] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Experiment for Molecule Alteration |
FISH assay; Next-generation sequencing assay | |||
Experiment for Drug Resistance |
Progression-free survival assay | |||
Mechanism Description | Alterations in the drug target comprising ALk mutations and ALk copy number gain have been described in approximately 30-45% of crizotinib-resistant cases. | |||
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) | [20] | |||
Molecule Alteration | Missense mutation | p.D816G |
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Resistant Disease | Lung adenocarcinoma [ICD-11: 2C25.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | Cell proliferation | Activation | hsa05200 | |
Experiment for Molecule Alteration |
FISH analysis; Sanger sequencing assay; Multiplex single nucleotide base extension assay | |||
Experiment for Drug Resistance |
MTS cellular proliferation assay | |||
Mechanism Description | An activating mutation in the kIT proto-oncogene receptor tyrosine kinase (kIT) (p.D816G) was identified by SNaPshot sequencing in a tumor sample from a patient with ROS1-positive NSCLC identified by fluorescence in situ hybridization whose disease progressed after initial response to crizotinib. kITD816G is an activating mutation that induces autophosphorylation and cell proliferation. |
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | ||||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) | [21] | |||
Molecule Alteration | Expression | Down-regulation |
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Sensitive Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Activation | hsa04210 | |
Cell colony | Inhibition | hsa05200 | ||
Cell invasion | Inhibition | hsa05200 | ||
Cell viability | Inhibition | hsa05200 | ||
ULk1 signaling pathway | Inhibition | hsa04211 | ||
In Vitro Model | U251 cells | Brain | Homo sapiens (Human) | CVCL_0021 |
In Vivo Model | Nude mouse model | Mus musculus | ||
Experiment for Molecule Alteration |
qRT-PCR | |||
Experiment for Drug Resistance |
MTT assay; TUNEL assay; Flow cytometry assay | |||
Mechanism Description | Silencing of LncRNA-HOTAIR decreases drug resistance of Non-Small Cell Lung Cancer cells by inactivating autophagy via suppressing the phosphorylation of ULk1. | |||
Regulation by the Disease Microenvironment (RTDM) | ||||
Key Molecule: hsa-mir-200c | [22] | |||
Molecule Alteration | Expression | Up-regulation |
||
Sensitive Disease | Lung cancer [ICD-11: 2C25.5] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
In Vitro Model | A549 cells | Lung | Homo sapiens (Human) | CVCL_0023 |
H460 cells | Lung | Homo sapiens (Human) | CVCL_0459 | |
NCI-2228 cells | Lung | Homo sapiens (Human) | CVCL_1543 | |
NCI-2228/CRI cells | Lung | Homo sapiens (Human) | CVCL_1543 | |
Experiment for Molecule Alteration |
RT-qPCR | |||
Experiment for Drug Resistance |
MTT assay | |||
Mechanism Description | miR200c regulates crizotinib-resistant ALk-positive lung cancer cells by reversing epithelial-mesenchymal transition via targeting ZEB1. | |||
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) | [22] | |||
Molecule Alteration | Expression | Down-regulation |
||
Sensitive Disease | Lung cancer [ICD-11: 2C25.5] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
In Vitro Model | A549 cells | Lung | Homo sapiens (Human) | CVCL_0023 |
H460 cells | Lung | Homo sapiens (Human) | CVCL_0459 | |
NCI-2228 cells | Lung | Homo sapiens (Human) | CVCL_1543 | |
NCI-2228/CRI cells | Lung | Homo sapiens (Human) | CVCL_1543 | |
Experiment for Molecule Alteration |
Western blot analysis | |||
Experiment for Drug Resistance |
MTT assay | |||
Mechanism Description | miR200c regulates crizotinib-resistant ALk-positive lung cancer cells by reversing epithelial-mesenchymal transition via targeting ZEB1. | |||
Unusual Activation of Pro-survival Pathway (UAPP) | ||||
Key Molecule: Serine/threonine-protein kinase ULK1 (ULK1) | [21] | |||
Molecule Alteration | Phosphorylation | Down-regulation |
||
Sensitive Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Activation | hsa04210 | |
Cell colony | Inhibition | hsa05200 | ||
Cell viability | Inhibition | hsa05200 | ||
ULk1 signaling pathway | Inhibition | hsa04211 | ||
In Vitro Model | U251 cells | Brain | Homo sapiens (Human) | CVCL_0021 |
In Vivo Model | Nude mouse model | Mus musculus | ||
Experiment for Molecule Alteration |
Western blot analysis | |||
Experiment for Drug Resistance |
MTT assay; TUNEL assay; Flow cytometry assay | |||
Mechanism Description | Silencing of LncRNA-HOTAIR decreases drug resistance of Non-Small Cell Lung Cancer cells by inactivating autophagy via suppressing the phosphorylation of ULk1. |
References
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