Transcript Targeting the PI-3 Kinase Pathway Carlos L. Arteaga, M.D. Departments of Medicine and Cancer Biology Breast Cancer Research Program Vanderbilt Ingram Cancer Center Vanderbilt University.

Targeting the PI-3 Kinase Pathway
Carlos L. Arteaga, M.D.
Departments of Medicine and Cancer Biology
Breast Cancer Research Program
Vanderbilt Ingram Cancer Center
Vanderbilt University School of Medicine
June 5, 2011
The PI3K pathway is a genetic target in cancer
Growth
Factors
PI3K is the pathway most commonly mutated
in human cancer
HER2
RAS
Confers malignant transformation, tumor cell
invasion, enhanced angiogenesis and survival,
and drug resistance
PI3K
PTEN
LKB1
AKT
AMPK
TSC1/2
mTOR
S6K
Mechanisms of activation include amplification/
mutation of oncogenes, mutations in PIK3CA
and AKT, and loss of tumor suppressors PTEN
and LKB1
Tumor suppressor gene
Oncogene
PIK3CA (p110a) mutations in human cancer
Samuels et al. Science 304:554, 2004
MCF10A cells
Vector
Wild-type
E545K
H1047R
Control
BEZ235
Amplified RTKs (HER2, EGFRmut) depend on PI3Ka
PIK3CA
+/+
-/-
RTK activated
Vector
HER2
RTK activation
•
EGFRmut
Leads to dependence on PI3K
Question:
If HER2 signaling depends on alpha
– why does PTEN loss create
trastuzumab resistance?
PIK3CAmut
Zhao et al. PNAS 2007
Loss of PTEN phosphatase results in PI3K dependence
PTEN-null
Pten-/- x
Ctrl
Pik3ca-/- Pik3cb-/-
Summary
 PTEN loss leads to constitutive AKT
activation
 PTEN loss leads to AKT dependence
(primarily AKT1)
 PTEN loss leads to PIK3CB
dependence
Jia et al. Nature 2008
PIK3CA mutant cells depend on p110a and are very sensitive to PI3Ki
shRNA
O’Brien et al. Clin. Cancer Res. 16:3670, 2010
PI3K pathway inhibitors
Drug
Source
Target(s)
BYL719
Novartis
PI3Kα
GDC-0032
Genentech
PI3Kα
INK-1117
Intellikine
PI3Kα
CAL-101
Calistoga
PI3Kd
XL-147
Exelixis/Sanofi
Pan-PI3K
BKM120
Novartis
Pan-PI3K
GDC-0941
Genentech
Pan-PI3K
PKI-587
Pfizer
Pan-PI3K
XL-765
Exelixis/Sanofi
PI3K/mTOR
BEZ235
Novartis
PI3K/mTOR
GDC-0980
Genentech
PI3K/mTOR
PF-4691502
Pfizer
PI3K/mTOR
INK-128
Intellikine
TORC1/2
OSI-027
OSI Pharma
TORC1/2
AZD8055
AstraZeneca
TORC1/2
AZD5363
AstraZeneca
AKT (catalytic)
MK-2206
Merck
AKT (allosteric)
GDC-0068
Genentech
AKT (catalytic)
Recent phase I trials data
BKM120
BEZ235
PI3K
PTEN
TORC2
PIP3
Akt
PDK1
Tuberin
BEZ235
Rheb
S6K
Akt function is required for insulin
signaling (C-peptide levels)
Most glycolytic enzymes are regulated
by the Akt/TOR pathway (FDG-PET)
TORC1
S6
XL147
4EBP1
Phase I Trials: Results (ASCO 2010)
Drug
MTD (doseC-peptide
limiting toxicity)
Tissue PD
biomarkers
FDG-PET
(SUV)
BKM120
(PI3Ki)
Yes (rash,
hyperglycemia)
↑ (long
term)
↓ P-S6 (skin)
↓
BEZ235
(PI3Ki &
mTORi)
No
↑ (short
term)
↓ P-S6 (tumor)
↓
Yes (rash,
hypersensitivity)
Unknown
↓ P-Akt, P-S6, P4EBP1 (tumor)
↓ (ASCO
2009)
XL147
(PI3Ki)
PI3K pathway alterations are not limited to hot spot mutations in
PIK3CA (p110a) and IHC can miss many alterations in the PTEN gene
PTEN IHC
Hot spot mutations
In PIK3CA (p110a)
E545K
H1047R
PTEN +
PTEN mutant (null)
PTEN mutant cells depend on p110b but not p110a
DOX sh-ctrl shPIK3CB
sh-ctrl shPIK3CB sh-ctrl shPIK3CB
+
PC3
DOX
+
sh-ctrl shPIK3CA
BT549
U87MG
 Inducible knockdown of p110a does not
alter AKT activity
 Inducible knockdown of p110b blocks
AKT activation
 Inducible knockdown of p110b blocks
anchorage independent growth
Wee et al. PNAS 105:13057, 2008
PI3K inhibitors have different potencies against p110 isozymes
IC50 (nM)
Family
Class I
PI3Ks
Class III
PI3Ks
Enzyme
BKM120
BEZ235
XL147
p110a
52 ± 37
4±2
39
p110a-H1047R
58 ± 2
4.6 ± 0.8
-
p110a-E545K
99 ± 6
5.7 ± 1
-
p110b
166 ± 29
75 ± 45
383
p110d
116
7±6
36
p110g
262 ± 94
5±4
23
mTOR
4610 ± 1860
20.7
>15000
DNAPK
>5000
-
4750
PI3K (p110) isozymespecific inhibitors
Drug
Source
Target(s)
BYL719
Novartis
PI3Kα
GDC-0032
Genentech
PI3Kα
INK-1117
Intellikine
PI3Kα
CAL-101
Calistoga
PI3Kd
XL-147
Exelixis/Sanofi
Pan-PI3K
BKM120
Novartis
Pan-PI3K
GDC-0941
Genentech
Pan-PI3K
PKI-587
Pfizer
Pan-PI3K
XL-765
Exelixis/Sanofi
PI3K/mTOR
BEZ235
Novartis
PI3K/mTOR
GDC-0980
Genentech
PI3K/mTOR
PF-4691502
Pfizer
PI3K/mTOR
INK-128
Intellikine
TORC1/2
OSI-027
OSI Pharma
TORC1/2
AZD8055
AstraZeneca
TORC1/2
AZD5363
AstraZeneca
AKT (catalytic)
MK-2206
Merck
AKT (allosteric)
GDC-0068
Genentech
AKT (catalytic)
Summary of Phase I Studies
• PI3K can be safely and at least partially inhibited in vivo
• Main toxicities: rash, hyperglycemia, fatigue, diarrhea
• Clinical activity was not limited to tumors with PIK3CA
hot spot mutations and PTEN loss by IHC and/or
sequencing
• But not all lesions in the PI3K pathway were profiled (i.e.,
AKT, p85a, PTEN mutations missed by IHC, PIK3CA
gene amplification, etc.)
• Changes in FDG-PET and inhibition of P-Akt and P-S6
by IHC appear to be good pharmacodynamic markers of
PI3K pathway inactivation
Frequency of mutations in the PIK3CA and
PTEN genes in 1,261 human breast cancers
AM González-Angulo and GB Mills, MD Anderson
Mutant PIK3CA or loss of PTEN confer resistance to trastuzumab
Trastuz.
Ctrl
PTEN shRNA
caPIK3CA
-
+
Ctrl
+
Berns et al. Cancer Cell 12:395, 2007
PIK3CA wt PIK3CA H1047R
PIK3CA mutations correlate with lack of pathological
complete response after neoadjuvant trastuzumab
trastuzumab
baseline1 wk biopsy
trastuzumab + docetaxel
surgery
3 wk biopsy
PIK3CA
Path
response
Mutant
WT
Yes
1
(14.3%)
12
(44.4%)
No
6
(85.7%)
15
(55.6%)
p= 0.11
Mohsin et al. JCO 23:2460, 2005; Dave et al. JCO 29:166, 2011
Presurgical clinical trial of letrozole in ER+/HER2−
operable breast cancer (Vanderbilt)
a-estrogenresistant
25%
a-estrogensensitive
Post-letrozole Ki67
<1%
Activating mutations in PIK3CA (p110a) correlate with a
lower reduction in Ki67 (mechanism of resistance?)
Combined inhibition of ER and PI3K induces complete
regressions of ER+/PIK3CA-mutant br ca xenografts
Miller et al. Submitted
Targeting the PI3K Pathway: Burning Questions
• Best approach to inhibit the pathway?
– PI3K vs. AKT vs. TORC1/2 vs. dual
PI3K/TOR inhibitor
– Will toxicity be different?
– Will activity dependent on specific
mutations?
– PTEN loss vs. PIK3CA mutations?
– Will p110 isozyme-specific inhibitors be
less toxic?
• Patient selection
– Should we select patients with mutations
in the PI3K pathway?
• Activation of compensatory pathways
– Combinatorial approaches
– Anti-HER2/HER3
– Hormonal therapy
– MEK inhibitors
– IGF-IR inhibitors