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Zhenghe John Wang | 07/12/2013

Targeting Mutant p110 α -specific Protein Interaction for Cancer Therapy . Zhenghe John Wang | 07/12/2013. The PI3K–AKT pathway. Mutant PIK3CA/ p110 α is an excellent target for precision cancer therapy. E545K. H1047R. Samuels Y, Wang Z, …Markowitz S et al . , Science, 2004.

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Zhenghe John Wang | 07/12/2013

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  1. Targeting Mutant p110α-specific Protein Interaction for Cancer Therapy • Zhenghe John Wang|07/12/2013

  2. The PI3K–AKT pathway

  3. Mutant PIK3CA/p110α is an excellent target for precision cancer therapy E545K H1047R Samuels Y, Wang Z, …Markowitz S et al., Science, 2004

  4. Challenges of targeting mutant p110α Vadas et al, Science Signaling 4(195) re2 Liu P et al, Nat Rev Drug Discov. 2009 The ATP binding pockets of p110α, β,γ and δ almost identical It is difficult to develop p110α-isoform-specific inhibitors Even harder to develop specific inhibitors against mutant p110α

  5. Hot spot mutations of PIK3CA/p110α E545K H1047R Samuels Y, Wang Z, Markowitz et al., Science, 2004

  6. Tagging WT or mutant PIK3CA

  7. p110a E545K associates with IRS1

  8. PIK3CA/p110α is the most frequently mutated oncogene in human cancers E545K H1047R Samuels Y, Wang Z, …Markowitz et al., Science,2004

  9. Association between IRS1 and various cancer-derived p110 mutant proteins

  10. IRS1-p110α helical domain mutant interaction is independent of p85 IRS1-p110α mutant interaction stabilizes p110α E545K and brings it to the membrane Hao et al, Cancer Cell 2013; 23:583

  11. WT p110α signaling Growth factor PIP2 RTK AKT activation IRS1 PIP3 p110α p85

  12. Mechanism of constitutive activation of p110α helical domain mutant proteins PIP3 PIP2 P110α IRS1 AKT activation p85 Hao et al, Cancer Cell 2013; 23:583

  13. p110α mutant

  14. A p110α mutant peptide interfere with p110 E545K-IRS1 interaction P110α E545K Mutant SEITKQEKDFLWSHRHYC WT SEITEQEKDFLWSHRHYC

  15. Peptide hydrocarbon stapling • Stabilizing secondary structures • Cell permeable • Protease-resistant

  16. The stapled p110α peptides Mutant WT

  17. Mutant p110 stapled peptides disrupt p110 E545K-IRS1 interaction Peptides added into culture cells

  18. Mutant p110 stapled peptide reduces AKT activity in p110α E545K mutant cancer Helical domain mutation Kinase domain mutation

  19. Mutant stapled peptide inhibits xenograft growth of p110 E545K tumors

  20. Mutant stapled peptide does not inhibit xenograft growth of p110 H1047R tumors

  21. Summary The p110α helical domain mutations rewire oncogenic signaling--- a new concept. Targeting the p110 mutant-IRS1 interaction provides a unique opportunity for cancer therapy.

  22. Future directions Stabilizing the mutant stapled peptide Nanoparticle (collaborate with Lu lab in BME) Peptidomimetics (with WeipingZheng in China) Screening for compounds that disrupt mutant p110α-IRS1 protein-protein interaction

  23. Schematic of Luciferase PCA for drug screening nGluc nGluc cGluc cGluc Compound IRS1 IRS1 P110αE545K P110αE545K

  24. Acknowledgements Wang Lab Collaborators U Akron WeipingZheng Brett Hirsch Case Sandy Markowitz Lili Liu Rob Ewing David Sedwick YujunHaoposter #2 Chao Wang Bo Cao Xiujing Feng Tony Scott poster #4 Shuliang Zhao Min Xiang

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