Imatinib, Gleevec, Glivec - ilte-cml.org · Imatinib, Gleevec, Glivec . Survival of CML patients...

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