09/10/2018
The Promise of Genotype-Directed Therapy
ALK / ROS fusions
crizotinib, alectinib
Unspecific Treatment
EGFR mutation
erlotinib, gefitinib
Lung Cancer
BRAF mutation
vemurafenib, dabrafenib
Imatinib, Gleevec, Glivec
Survival of CML patients
before and after imatinib
6 years
Activity of Crizotinib in ALK+ NSCLC Phase III Study
Darwinian Evolution
Darwinian Evolution
Darwinian Evolution
Darwinian Evolution
Darwinian Cancer Evolution
Evolution of Disease Under
Drug Pressure
Drug-tolerant persister cells
Drug Resistance
TARGET-DEPENDENT TARGET MUTATION
BINDING CONFORMATION
TARGET AMPLIFICATION
TARGET-INDEPENDENT MULTI-DRUG RESISTANCE BY-PASS
MUTATION ADAPTIVE
Drug Resistance
TARGET-DEPENDENT TARGET MUTATION
BINDING CONFORMATION
TARGET AMPLIFICATION
TARGET-INDEPENDENT MULTI-DRUG RESISTANCE BY-PASS
MUTATION ADAPTIVE
Target Mutation
Target Mutation
ATP/drug binding site in
Protein Kinases
ATP/drug binding site in
Protein Kinases
ATP/drug binding site in
Protein Kinases
BCR-ABL BCR-ABLT315I
Imatinib in ABL pocket
Target Mutation
BCR-ABL
Target Mutation
NPM-ALK
Target Mutation
C1156Y
L1196M
TARGET MUTATION
Target Mutation
Target Mutation
Target Mutation
EGFR
ACTIVE INACTIVE
Target
Conformation
HYDROPHOBIC REGULATORY SPINE
ALK
RAS/RAF/MAPK pathway Ras
Raf
MEK
ERK
PROLIFERATION
Braf-V600E
MEK
ERK
PROLIFERATION CELL DEATH
Allosteric Mutation
BRAF
Allosteric Mutation
BRAF
Drug Resistance
TARGET-DEPENDENT TARGET MUTATION
BINDING CONFORMATION
TARGET AMPLIFICATION
TARGET-INDEPENDENT MULTI-DRUG RESISTANCE BY-PASS
MUTATION ADAPTIVE
Target Amplification
oncogene oncogene oncogene oncogene
Gene amplification
Abl
actin
Target Amplification
BCR-ABL
LeCoutre et al., Blood 2000
Target Amplification
NPM-ALK
NP
M-A
LK e
xpre
ssio
n
Ceccon et al., Mol Can Res 2015
Drug Addiction
Drug Resistance
TARGET-DEPENDENT TARGET MUTATION
BINDING CONFORMATION
TARGET AMPLIFICATION
TARGET-INDEPENDENT MULTI-DRUG RESISTANCE BY-PASS
MUTATION ADAPTIVE
P-GLYCOPROTEIN
Multi-Drug Resistance
Drug Resistance
TARGET-DEPENDENT TARGET MUTATION
BINDING CONFORMATION
TARGET AMPLIFICATION
TARGET-INDEPENDENT MULTI-DRUG RESISTANCE BY-PASS
MUTATION ADAPTIVE
By-pass Pathways
Ras
Raf
MEK
ERK
PROLIFERATION
Braf-V600E
MEK
ERK
PROLIFERATION CELL DEATH
By-pass Pathways
Braf-V600E
MEK
ERK
PROLIFERATION CELL DEATH
By-pass Pathways
Craf
Ras
PROLIFERATION
Braf-V600E
MEK
ERK
PROLIFERATION CELL DEATH
By-pass Pathways
Craf
PROLIFERATION
Craf
Craf
Craf
Braf-V600E
MEK
ERK
PROLIFERATION CELL DEATH
By-pass Pathways
PROLIFERATION
COT
Braf-V600E
ERK
PROLIFERATION CELL DEATH
By-pass Pathways
MEK
PROLIFERATION
MEK
Adaptive Response
Ligand-induced by-pass
Relieve of negative feedback
Adaptive Response
Relieve of negative feedback
Adaptive Response
SUMMARY
1.target mutation
2. by-pass
Recommended
