Drug (ID: DG00050) and It's Reported Resistant Information
Name
Crizotinib
Synonyms
Xalkori (TN); novel ALK inhibitors
    Click to Show/Hide
Indication
In total 1 Indication(s)
Lung cancer [ICD-11: 2C25]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Brain cancer [ICD-11: 2A00]
[2]
Lung cancer [ICD-11: 2C25]
[3], [4], [5]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Lung cancer [ICD-11: 2C25]
[1]
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
IsoSMILES
C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N
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
InChIKey
KTEIFNKAUNYNJU-GFCCVEGCSA-N
PubChem CID
11626560
ChEBI ID
CHEBI:64310
TTD Drug ID
D03ZBT
VARIDT ID
DR00523
INTEDE ID
DR0387
DrugBank ID
DB08865
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
Click to Show/Hide the Resistance Disease of This Class
Brain cancer [ICD-11: 2A00]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [6]
Molecule Alteration Missense mutation
p.F1174L
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) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [2]
Molecule Alteration Missense mutation
p.F1174L
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]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [7], [8], [9]
Molecule Alteration Missense mutation
p.S1206Y
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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) Click to Show/Hide
Key Molecule: hsa-miR-100-5p [1]
Molecule Alteration Expression
Up-regulation
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) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8]
Molecule Alteration Structural variation
Copy number gain
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
.
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
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) Click to Show/Hide
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [21]
Molecule Alteration Expression
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 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) Click to Show/Hide
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) Click to Show/Hide
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
Ref 1 miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC. Biochem Biophys Res Commun. 2019 Apr 2;511(2):260-265. doi: 10.1016/j.bbrc.2019.02.016. Epub 2019 Feb 18.
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