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2/19/13
1
Squamous Cell Carcinomas: Genomic Discovery and Biomarkers
Peter Hammerman MD, PhDDana Farber Cancer Institute
Treatment of Advanced NSCLCAdenocarcinoma Squamous Cell
No Tumor GenotypingChemotherapy
Targeted agents largely ineffective to date
Tumor GenotypingPersonalized Therapy
KRASUnknown
g g g y
EGFR
ALKB
RA
F
PIK
3CA
ER
BB
2
RO
S1
RET
AK
T1
MA
P2K
1
2/19/13
2
2012—Year of retrospective NGS studies of lung cancer
A second screen–SNP array analysis demonstrates amplification of FGFR1 in 6% of NSCLC (45/733):3% of adenocarcinomas and 20% of squamous carcinomas
WHSC1L1
FGFR1
FLJ43582
Weiss et al and Dutt et al
2/19/13
3
FGFR1 amplification predicts sensitivity to FGFR kinase inhibitors in some cell lines
Phase I of BGJ398 presented at AACRResponses in FGFR1 amplified lung SqCC, one >6 mos
MYCLMCL1
RELNFE2L2
SOX2PDGFRA
TCGA LUSC Amplifications
PDGFRA
EGFRFGFR1
CCND1CCND1
CRKL
ERBB2
MDM2
2/19/13
4
FGFR2/3 Mutations in Lung SqCC
FGFR-driven transformation is blocked by multiple FGFR kinase inhibitors
BGJ398 Ponatinib
2/19/13
5
Ba/F3 Cell Profiling of FGFR2 mutations reveals sensitivity to a panel of inhibitors
100W290Cb
W290Cc
S320Cb
K660Ebon
100 W290Cb
W290Cc
S320Cb
n
-3 -2 -1 0 10
50
K660Eb
K660Ec
K660Nb
K660Nc
WT2b
EGFR insNPG
Ba/F3 +IL3
Log uM BGJ398
Gro
wth
inh
ibiti
o
-3 -2 -1 0 10
50
K660Eb
K660Ec
K660Nb
K660Nc
WT2b
EGFR insNPG
Ba/F3 +IL3
Log uM AZD4547
Gro
wth
inh
ibiti
on
Response to pazopanib in a patient with a FGFR2 mutation
FGFR2 P253R
2 weeks pazopanib
2/19/13
6
Revisiting the kinome by exome sequencing
Radiographic response of a patient with a S768R DDR2 mutation treated with dasatinib plus erlotinib.
2/19/13
7
40
60
80
100
13
2
atio
ns/M
b
Syn.Non syn
Syn.MissenseSplice siteNonsense
Frame shiftIn frame indelOther non syn.
Significantly Mutated Genes in Lung Sqcc
7%
8%
15%
3%
20%
12%
16%
8%
15%
81%551 551
70 50 30 10# individuals with mutation
0.5 2.0 3.5
RB1
NOTCH1
NFE2L2
HLA-A
MLL2
KEAP1
PIK3CA
PTEN
CDKN2A
TP53
-log10(q-value)
0
20
40
# m
utaNon syn. Nonsense
g (q )
NFE2L2/KEAP1/CUL3 Mutations in KEAP1 are lof (frequent LOH of second allele)
Mutations in NRF2 cluster in DLG and ETGE motif -> prevent KEAP1 interaction -> results in NRF2 stabilization and nuclear entry
Shibata et al. PNAS 2008
In head and neck cancer mutations in NFE2L2/KEAP1/CUL3 are mutually exclusive with HPV+ (p<0.02); TP53 (p=0), CDKN2A (p<0.001)
2/19/13
8
500 1000 2000 cells 500 1000 2000 cells
A549 H460
2 KEAP1 mutant lung cancer lines are sensitive to siRNA targeting NFE2L2
A549 H460
siNTC
siNRF2
siNTC
siNRF2
GAPDH
siNTC-D3
siNRF2-D3
siNTC-D7
siNRF2-D7
siNTC-D3
siNRF2-D3
siNTC-D7
siNRF2-D7
NRF2
Mohamed Abazeed
NRF2 Mutant SCC Line
1000 2000 4000 #cells
LK2
siNTC
siNRF2
120 00
NRF2 gene exp. with siNRF2 KD in LK2 cells
120 00
NQO1 gene exp. with siNRF2 KD in LK2 cells
NRF2
GAPDH
siNTC-D6
siNRF2-D6
100.0
6.2
0.00
20.00
40.00
60.00
80.00
100.00
120.00
siNTC-D6 siNRF2-D6
Rel
ativ
e E
xpre
ssio
n
100.0
13.2
0.00
20.00
40.00
60.00
80.00
100.00
120.00
siNTC-D6 siNRF2-D6
Rel
ativ
e E
xpre
ssio
n
2/19/13
9
Radiosensitization with PI3K antagonism
Lung Squamous
Immunotherapeutic Biomarkers
Head and neck Squamous
2/19/13
10
Summary—Lung Sqamous Cell Cancer
• Most altered RTK pathway in lung SqCC is FGFRFGFRs
• Most altered kinase pathway is PI3K• Role for PI3K antagonists in personalized
radiotherapyLikely will be a role for personalized• Likely will be a role for personalized immunotherapy
• Genotype interactions in many dimensions should inform therapeutic decision making
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