Growth Factor Receptor EGFR mutants and its Clinical Implications Jeonghee Cho Samsung Genome Institute Samsung Medical Center Outline Mechanistic insight of cetuximab based EGFR targeted therapy ID: 813405
Download The PPT/PDF document "Mechanistic Insights into Oncogenic Acti..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Mechanistic Insights into Oncogenic Activation of Epidermal Growth Factor Receptor (EGFR) mutants and its Clinical Implications
Jeonghee Cho
Samsung
Genome Institute
Samsung Medical Center
Slide2Outline
Mechanistic insight of
cetuximab
-based EGFR targeted therapy
2. Novel mechanism of RTK activation and clinical implication
3. Ongoing projects (preliminary data)
- Integrated genomic approaches for studies of erlotinib-resistance
mechanism
- Novel drug target pipeline (proof of principle)
Cancer is a Complex Genetic Disease
Current model of cancer development
Somatic Alterations of the Genome
Altered Function or Expression of
Oncogenes
/
Tumor Suppressor Genes
Cancer Cell Phenotypes
Point Mutations
Copy Number Alterations
Chromosomal Rearrangements
Epigenetic Modifications
Infections
Uncontrolled proliferation
Prolonged survival
ImmortalizationAngiogenesisInvasion/Metastasis
Hanahan and Weinberg,
Cell
(2000 & 2010)
Slide4Why Study Cancer Genomes?
1. Discover
novel genes
and
pathways
important for cancer development
2. Develop a natural
classification scheme
for human cancers 3. Identify targets for therapeutic intervention
Example
: Activating point mutations in EGFR kinase domain in a subset of NSCLC patients predicts sensitivity to EGFR kinase inhibition
Slide5Somatic EGFR mutations found in ~30% of East Asian lung adenocarcinomas, ~7-10% of U.S.
and European patients
Clustered in four areas
Nucleotide binding (P loop), G719
Exon 19 deletions
Exon 20 insertions
(C-terminal to alpha helix)
Activation loop mutations (L858)Mutation status predictive of clinical response to gefitinib, erlotinibEx19 deletions L858R
EGFR mutations in Lung Cancer
Frequency of mutation
by exon
EGFR kinase domain
mutations
Paze et al. 2004 Science
Exon 21
41%
Exon 18
5%
Exon 19
48%
Exon 20
6%
Slide6E
pidermal
G
rowth
F
actor
R
eceptor (EGFR)
Extracellular domain
Kinase domain
C-terminal tail
1
645
669
706
979
1210
Transmembrane
segment
Juxtamembrane
segment
P
P
P
P
P
The EGFR pathway
EGFR dimers and their ligands
Okines, A.
et al
.
Nat. Rev. Clin. Oncol. (2011)
Slide7EGFR mutations in Lung Cancer
Slide8Mutant EGFRs identified from Lung Cancers and
Glioblastoma are oncogenic.
Greulich H. et al. PLoS Med (2005)
Cho J. et al. Cancer Research (2011)
Slide9Anti-EGFR Targeted therapeutic approaches
Tyrosine kinase inhibitors (TKIs)
Gefitinib and erlotinib
- Effective against mutant EGFR
- Develop acquired resistance (T790M,
MET amplification)
HKI-272 and BIBW2992 - EGFR and ErbB2 irreversible inhibitor - Effective against T790M mutant in vitro - Ongoing clinical trials with stage IIIB or IV NSCLC
Monoclonal antibody
Cetuximab (Erbitux)
- human-mouse chimeric EGFR monoclonal antibody
- Improve overall survival in clinical trial with chemotherapy in NSCLC (FLEX study) - EGFR characteristics that correlate with tumor sensitivity are not known. - Molecular mechanism of antitumor activity of cetuximab is not clear. (disruption of dimerization or/and ADCC and/or downregulation of EGFR)
Slide10C-terminal deletion mediated oncogenic activation of EGFR
Slide11Concentration (μg/ml)
Cell Viability (% control)
Cell Viability (% control)
Concentration (μM)
Tarceva
Cetuximab
GBM-derived CT deletion EGFR mutants are sensitive to cetuximab and erlotinib
in vitro
Slide12Intracranial GBM mouse model
LN443 cells expressing
CT Del1, CT1009, vIII and WT
Slide13Cho J.
et al
, Cancer Research (2011)
Cetuximab prolonged survival of mouse harboring brain
tumors induced by GBM-derived oncogenic EGFR mutants.
Slide14EGFR exon25&26 deletion mutation identified by WGS
in lung adenocarcinoma is oncogenic and sensitive to erlotinib
Kyusam Choi and Jeonghee Cho
Imielinski
et al
. (
Cell
, 2013)