Download a housekeeping protein highjacked by cancer cells

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