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The Hsp90 Molecular Chaperone: A Housekeeping Protein Highjacked by Cancer Cells Len Neckers Urologic Oncology Branch Len Neckers, PhD I/We have no real or apparent conflicts of interest to report, and I will be discussing non-approved (in the US) investigational drugs Why Target Hsp90 in Cancer? Normal Cells (Maintains Protein Homeostasis) Hsp90 Cancer Cells (Maintains Functionality/Stability of Mutated and/or Over-Expressed Oncogenes) Hsp90 senses environmental stress & coordinates cellular responses to promote survival Evading Immune Destruction Epha2 Telomerase Nutrient Stress Limitless Replicative Potential Src VEGF MET Proteotoxic Stress Sustained Angiogenesis HIF Other RTKs Hypoxia Hsp90 Tissue Invasion & Metastasis MMP2 urokinase CDK4 Insensitivity to Antigrowth Signals Genetic Instability/Aneuploidy CDK6 cyclinD IGF-1R Evading Apoptosis AKT HER2 Self-sufficiency in Growth Signals KIT ALK Other RTKs Reprogramming of Energy Metabolism HIF Glycolysis 2008 Loss of 14q32.2-32.33 chromosomal region and HSP90 expression correlates negatively with survival in NSCLC HSP90 expression and survival in three validation sets of NSCLC patients Amplification and high‐level expression of HSP90 marks aggressive phenotypes of HER2 negative breast cancer Qing Cheng1*, Jeffrey T. Chang5, Joseph Geradts 2, Leonard M. Neckers6, Timothy Haystead3, Neil L. Spector 4, H. Kim Lyerly1,2* Results: Up-regulated HSP90 [in tumor] significantly increased the risk of recurrence and distant metastasis in patients with a variety of molecular subtypes of cancer including triple-negative and HER2-/ER+ breast cancer. Cheng et al. Breast Cancer Res. 2012 Hypothesis: inhibiting Hsp90 compromises cancer cell robustness and may impact resistance to other therapies Cowen LE. The fungal Achilles’ heel: targeting Hsp90 to cripple fungal pathogens. Curr Opin Microbiol; 2013, 16:377 Geller R, Andino R, Frydman J. Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLOS ONE; 2013, 8:e56762 ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo Complex twist & turns of the chaperone cycle open ATP-bound DRUGS N CL ATP ATP ATP M Client proteins degraded by proteasome C ADP closed & twisted ADP ADP ATP ATP ATP ATP ATP ATP Pi Neckers et al (2009) Nat. Stuct. Mol. Biol. Trepel et al (2010) Nature Reviews Cancer EML4-ALK is very sensitive to Hsp90 inhibition Total & phospho-EML4-ALK Chen et al. Cancer Res, 2010 Normant et al., Oncogene, 2011 Hsp90 Monotherapy: A Novel Strategy To Inhibit Oncogenic Kinases Hsp90i Clinical development of HSP90 inhibitors Neckers and Trepel Clin Cancer Res 2014 Hsp90 inhibitors synergize with tyrosine kinase inhibitors and even partially reverse TKI resistance MET Miyajima et al. Cancer Research, 2013 MET TKI and HSP90 inhibitor synergize in wild-type MET-overexpressing cells MET TKI and HSP90 inhibitor synergize in TKI-resistant MET mutant-expressing cells MET TKI and HSP90 inhibitor synergistically inhibit tumor growth in MET-driven tumor xenografts HER2+ Breast Cancer: 17-AAG + Herceptin in Patients Who Progressed on Herceptin Alone 60 % change from baseline 40 20 0 -20 -40 -60 -80 ResponseCode Code Response Progressive Disease Progressive Disease Stable Disease Stable Disease Partial Response Partial Response -100 Response rate: 26%; overall clinical benefit rate: 63% Modi et al., Clin Cancer Res, 2011 Wong et al. ASCO, 2011 Socinski, et al. A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with genotypically Defined Advanced Non–Small Cell Lung Cancer. Clin Cancer Res; 2013 With respect to RAS… De Raedt, et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell, 2011 Acquaviva, et al. Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib. Mol Cancer Ther, 2012 In both cases, combination with mTOR inhibition was most effective… The relationship between Ras-driven signaling, ROS, Hsp90, and ER stress Marcu, et al. Mol Cell Biol, 2002 De Raedt, et al. Cancer Cell, 2011 HSF1 Xu, Trepel, Neckers Cancer Cell 2011 Acquaviva, et al., Mol Cancer Res, 2014; Chou, et al. PLoS One, 2012 TCGA-NSCLC: KRAS and Kinases • KRAS is altered in 35% of all cases • 12 kinases that interact with HSP90 are altered in 82.2% of all cases • Alterations in 89.1% of all cases combined Each column is a separate case • Red bar: Amplification • Red box: mRNA Upregulation • Green square: Mutation • Blue bar: Homozygous Deletion • Blue box: mRNA Downregulation • Black arrow: Fusion Thomas Prince & Harvey Schwartz Thoughts on how to improve future clinical development of Hsp90 inhibitors: • Optimal schedule: take advantage of significant drug retention in tumors vs normal tissues (avoid client rebound & normal tissue effects) • Dynamic PD: image the client (e.g., RTKs by PET - herceptin) use to optimize schedule measuring PD in tumor highly preferable to using surrogate (e.g., normal) tissue such as PBMC • Target HSF1 to prevent Hsp70 induction: mTOR inhibitors (others?) • Use Hsp90 inhibitors in combination based on tumor molecular profile
