Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants

1. Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants

2. Diseased Genome Hospital http://blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg

3. http://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpghttp://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg

4. http://img.quamut.com/chart/9471/02_healthy_sick_x-ray.jpg

5. http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=yhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

6. Where Are We Headed? http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg

7. Cancer http://www.odec.ca/projects/2005/thog5n0/public_html/Tumour.gif

8. History of Lung Cancer http://www.icowman.com/uploadfiles/2007072409225175.jpg http://www.icowman.com/uploadfiles/2007072409225175.jpg

9. Pathology Non Small Cell Small Cell Bronchi Grows rapidly Spreads quickly • Squamous cell carcinoma • Adenocarcinoma • Large-cell carcinoma http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/ Lynch et al., (2004) http://images.google.com/imgres?imgurl=http://www.dkimages.com/discover/previews/852/20223038.JPG

10. Risk Factors http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

11. You Are Not Alone • This year approximately 200,000 people will be diagnosed with lung cancer • NSCLC accounts for 80% of all lung cancers http://www.cdc.gov/cancer/lung/statistics/ http://seo2.0.onreact.com/wp-content/uploads/2008/09/you-re-not-alone.jpg

12. Epidemiology http://medicineworld.org/cancer/lung/ http://images.google.com/

13. What Next? While there is no known cure as of right now, there ARE options! Imatinib Gefinitib Cisplatin http://dspace.mit.edu http://dspace.mit.edu

14. EGF ERBB2 Cisplatin Imatinib Protein Cascade Gefitinib EGFR P ? Nucleus ?

15. P VEGF-A EGF MET P ERBB2 P PI3K Imatinib Cisplatin Gefitinib Protein Cascade Protein Cascade EGFR P AKT PDGFR P Nucleus

16. Implications of Chromosomal Loci in the Development of Lung Cancer http://academic.evergreen.edu http://rosenblumtv.files.wordpress.com http://www.pharmgkb.org

17. Chromosomes • Compact structures of DNA • Contains thousands of genes Chromatid Centromere Genes http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif

18. Single Nucleotide Polymorphisms (SNPs) • Single variation in nucleotide base pairs • Alleles are a result of SNPs within gene sequence • SNP’s are the basis for lung cancer susceptibility http://www.dnalandmarks.com/english/pictures/what_are_snps.jpg

19. Genome-wide Association Studies • Variation across genomes • Genotype cases along with controls • Find roles that genes play in disease • Large sample sizes http://www.blog.speculist.com/archives/dna2two

20. Identifying Regions On Chromosomes 6 Regions Away p-arm Centromere Region 5q6 q-arm 5 http://images.google.com/

21. Three Regions of Association http://upload.wikimedia.org/ http://upload.wikimedia.org/

22. Nicotinic Acetylcholine Receptor Genes Found on 15q24 and 15q25 http://www.jyi.org/articleimages/88/originals/img0.jpg Nicotine binds and stimulates acetylcholine ion channel-linked in neurons

23. How were these regions discovered? (Hung et al., 2008)

24. 15q24 highly linked with smoking behavior (Thorgeirson et al., 2008)

25. TERT gene found on 5p15.33 Cancerous Growth http://images.google.com/i

26. 5p15.33 shows similar results (McKay et al., 2008)

27. P VEGF-A EGF MET P ERBB2 P PI3K Imatinib Cisplatin Gefitinib Protein Cascade Protein Cascade EGFR P AKT PDGFR P Nucleus

28. How Do Cells Proliferate?

29. EGFR/ERBB2 Forms a Heterodimer EGFR EGFR EGF EGFR ERBB2 ERBB2 P P Proliferation Protein Cascade Survival Nucleus Apoptosis

30. How Can This Lead to Cancer?

31. Mutated EGFR Leads to Cancer ERBB2 EGFR P Protein Cascade Proliferation Nucleus

32. Mutated EGFRs have Distinct Patterns of Tyr Phosphorylation (Chen et al., 2006)

33. Tyrosine Kinase Inhibitors (TKIs)Gefitinib EGFR Tyrosine Kinase domain ATP TKI ATP binding cleft on the kinase

34. Gefitinib Suppresses Phosphorylation of Most EGFR Mutants (Chen et al., 2006)

35. What About the Proteins in the Signaling Pathway?

36. Effectiveness of Gefitinib is Dependent on Concentration (Pedersen et al., 2005)

37. High Doses of Gefitinib Decreases Proliferation of Mutated EGFR Cells (Pedersen et al., 2005)

38. Gefitinib has Variable Growth-Inhibitory Effects (Chen et al., 2006)

39. P VEGF-A EGF MET P ERBB2 P PI3K Imatinib Cisplatin Gefitinib Protein Cascade Protein Cascade EGFR P AKT PDGFR P Nucleus

40. What Are the Roles of Proteins Associated with Lung Cancer? http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

41. Recap Alanine N-terminus Tyrosine P P C-terminus P Nucleus Threonine Leucine Serine Lysine

42. How Does The Pathway Work?

43. Domain Attraction ERBB2 P P PI3K Protein Cascade SH2 Change in Gene Expression Nucleus

44. Why are EGFR and ERBB2 Special?

45. Main Contributors to NSCLC (Rikova et al. 2007)

46. Link between Concentration and Interaction (Jones et al. 2006) Green andBlue circles = Proteins involved in cascade Interactions Red lines = Red circles = EGFR Receptor

47. Other ERBB2 Associations No. protein receptors No. protein receptors No. protein receptors Affinity Threshold (nM) Affinity Threshold (nM) Affinity Threshold (nM) (Jones et al. 2006)

48. Are there other types of Proteins? http://en.wikipedia.org/wiki/Proteins

49. Other Contributors to NSCLC (Rikova et al. 2007)

50. Specifically, some proteins more than others Amount of overphosphorylated protein in samples Chart configured from Table1 of Rikova et al. 2007