1. Targeted therapies of cancer: Lessons from EGFR mutations in lung cancer
Daniel Haber MD PhD
Massachusetts General Hospital Cancer Center
Harvard Medical School

2. Trend toward molecularly targeted anti-cancer drugs
ONCOLOGY PRODUCTS 32 6 27
Hormonal 49 67
Cytotoxic
Targeted 18
Market Development
(McKinsey & Co., NY)

3. Molecular targeting of cancer.... finding the right fit

4. The Holy Grail: BCR-ABL, Imatinib and CML
Philadelphia chromosome
“tumor specific” kinase
BCR-ABL
C lobe
Inhibitor
Drug
Gleevec
Chronic Myeloid Leukemia

5. Receptor tyrosine kinases as drug targets
growth
factor
Receptor Tyrosine Kinase
ATP P K
Intracellular
kinase P P K
ATP P
BCR-ABL
signaling
cascade P P
substrate P P

6. Iressa/Tarceva-responsive lung cancer:
-- Mutations in EGFR near drug binding site
EGFR Mutations
Responders: % ( 74/95)
Nonresponders: 6% (6/106)
Correlated with
- Nonsmokers
- Women
- Asian ethnicity
- Adenocarcinoma
del L747-P753insS
del E746-A750
del L747-A750
L858R
N lobe
Inhibitor
C lobe

7. Genotype-directed therapy of lung cancer?
-Genetically defined NSCLC subset (~10%)....
Dramatic responses to Iressa (Gefitinib)/Tarceva (Erlotinib)
- EGFR mutations
- EGFR amplification (mutant + wild type allele)
- too infrequent to drive survival in large US studies
- 80% upfront responses and improved survival in Asia
Disease stabilization with Tarceva (Erlotinib)
- Other molecular markers...?
- Modest survival advantage in non-genotyped studies
- Drug dose (Iressa vs Tarceva)
-Majority of NSCLC....

8. Biochemical: Structural alteration in mutant receptor
Why are EGFR-mutant lung cancers exquisitely sensitive to small molecule EGFR inhibitors ?
Biochemical: Structural alteration in mutant receptor
-- Complete suppression of EGFR signaling at
clinically relevant dosing
Biological: Dependence on mutant EGFR for survival
-- Altered signaling by mutant receptor
-- “Oncogene Addiction” (Bernard Weinstein)

9. Acquired resistance to EGFR inhibitors
1. Recurrent T790M “Gatekeeper” Mutation
N lobe
T790M
Inhibitor
C lobe
Irreversible EGFR inhibitors
2. Reprogramming of cellular survival signals
Targeting multiple pathways?
-- eg. EGFR and MET
(Engelman and Janne)
Cell Signaling

10. Monitoring genotype during cancer therapy:
Isolation of circulating tumor cells by microfluidic immunocapture
Mehmet Toner, Sunitha Nagrath, Shyamala Maheswaran

11. Appearance of T790M drug resistance mutation in CTCs
Exon2
Del
T790M

12. How common are genetically definable drug susceptible
subsets of epithelial cancers ?
--- MET Amplification as marker for drug susceptibility
Subset of gastric/esophageal cancers with MET amplification:
-- Exquisite sensitivity of Amp+ cells to MET inhibitor
2. AKT survival signals are
driven by MET in Amp+ cells

13. High throughput drug screening
How common are genetically definable drug susceptible
subsets of epithelial cancers ?
--- Functional screen for drug susceptibility
~1100 human cancer cell lines panel
“genetic diversity of cancer”
Compounds 1-8
Compounds 9-16
Compounds 17-24
Con
MG-132
L-685,458
Taxol
Cisplatin
CL-387,785
HKI-272
AG-957
JAK2 inhibitor
Low
High
Medium
Drug Concentration
High throughput drug screening
Jeff Settleman

14. Range of tumor cell line sensitivity to kinase inhibitors
McDermott et al

15. NSCLC lines with greatest erlotinib sensitivity are enriched for EGFR mutations
Extremely sensitive
Highly sensitive
Moderately sensitive
Insensitive
Cell line Tissue Sensitivity EGFR status
McDermott et al

16. Sensitivity to the MET inhibitor correlates with MET amplification*
McDermott et al

17. Molecular targeted therapy of cancer
Challenges....
Identifying an “Achilles heel” for different subsets of
cancers in preclinical studies ?
Designing early phase clinical trials for genotype-directed
therapies?
Expectations from targeted therapies ?

18. Acknowledgements Jeff Settleman Tom Lynch Daphne Bell Shyamala
Maheswaran
Sree
Sharma
Mehmet
Toner
Lecia
Sequist
Raffaella Sordella
Eunice
Kwak
The “Iressa Team”
Ultan
McDermott
Gromek
Smolen
Nadia Godin-
Heymann