1. Samsung Genome Institute Samsung Medical Center
Mechanistic Insights into Oncogenic Activation of Epidermal
Growth Factor Receptor (EGFR) mutants and its Clinical Implications
Jeonghee Cho
Samsung Genome Institute
Samsung Medical Center
Thank you so much for invitation for 1

2. Outline 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)

3. Cancer is a Complex Genetic Disease
Current model of cancer development
Altered Function or Expression of Oncogenes/
Tumor Suppressor Genes
Cancer Cell Phenotypes
Somatic Alterations of the Genome
Point Mutations
Copy Number Alterations
Chromosomal Rearrangements
Epigenetic Modifications
Infections
Uncontrolled proliferation
Prolonged survival
Immortalization
Angiogenesis
Invasion/Metastasis
Hanahan and Weinberg, Cell (2000 & 2010)

4. Why 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

5. EGFR mutations in Lung Cancer
Somatic 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,
erlotinib
Ex19 deletions
L858R
Exon 18 5%
Exon 21
41%
Exon 19
48%
Exon 20 6%
EGFR kinase domain
mutations
Frequency of mutation
by exon
Paze et al Science 5

6. Okines, A. et al. Nat. Rev. Clin. Oncol. (2011)
Epidermal Growth Factor Receptor (EGFR)
Transmembrane
segment 1
645
669
706
979
1210
Extracellular domain
Kinase domain
C-terminal tail P P P P P
Juxtamembrane
segment
EGFR dimers and their ligands
The EGFR pathway
Okines, A. et al. Nat. Rev. Clin. Oncol. (2011)

7. EGFR mutations in Lung Cancer

8. Mutant EGFRs identified from Lung Cancers and
Glioblastoma are oncogenic.
Greulich H. et al. PLoS Med (2005)
Cho J. et al. Cancer Research (2011)

9. Anti-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)

10. C-terminal deletion mediated oncogenic activation of EGFR

11. GBM-derived CT deletion EGFR mutants are sensitive to cetuximab and erlotinib in vitro
Tarceva
Cetuximab
Concentration (μg/ml)
Cell Viability (% control)
Cell Viability (% control)
Concentration (μM)

12. Intracranial GBM mouse model
LN443 cells expressing
CT Del1, CT1009, vIII and WT

13. Cetuximab prolonged survival of mouse harboring brain
tumors induced by GBM-derived oncogenic EGFR mutants.
Cho J. et al, Cancer Research (2011)

14. EGFR 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)