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Mechanistic Insights into Oncogenic Activation of Epidermal Mechanistic Insights into Oncogenic Activation of Epidermal

Mechanistic Insights into Oncogenic Activation of Epidermal - PowerPoint Presentation

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Mechanistic Insights into Oncogenic Activation of Epidermal - PPT Presentation

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

cancer egfr mutations exon egfr cancer exon mutations cetuximab oncogenic lung kinase clinical cell activation erlotinib cho domain mechanism

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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

Slide2

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)

Slide3

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)

Slide4

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

Slide5

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, 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%

Slide6

E

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)

Slide7

EGFR mutations in Lung Cancer

Slide8

Mutant EGFRs identified from Lung Cancers and

Glioblastoma are oncogenic.

Greulich H. et al. PLoS Med (2005)

Cho J. et al. Cancer Research (2011)

Slide9

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)

Slide10

C-terminal deletion mediated oncogenic activation of EGFR

Slide11

Concentration (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

Slide12

Intracranial GBM mouse model

LN443 cells expressing

CT Del1, CT1009, vIII and WT

Slide13

Cho J.

et al

, Cancer Research (2011)

Cetuximab prolonged survival of mouse harboring brain

tumors induced by GBM-derived oncogenic EGFR mutants.

Slide14

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)