biology of driver oncogenes egfr, eml4-alk, ros1… tetsuya mitsudomi kinki university faculty of...
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Biology of Driver OncogenesEGFR, EML4-ALK, ROS1…
Tetsuya MitsudomiKinki University Faculty of Medicine
Perspectives in Lung Cancer5th Asian Pacific Conference
24-25 August, 2012, Hong Kong
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Interchromosomal translocation
Intrachromosomal translocation
LOH
Copy number gain
Copy number loss
一 single nucleotide variation
51 y/o male caucacian with smoking hxp/d adenocarcinomaKRAS mutation + 391 somatic mutation43 large-scale structural variants17.7 mutation/Mb
First adenocarcinoma genome
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Driver and Passenger
Passenger gene mutation
Neutral genetic changes that are unrelated to cancer development caused by
exposure to mutagens, or genetic instability or many
mitoses
Driver gene mutation
Gene mutation essential for cancer cell development, growth
or survival
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Tumor heterogeneity in Patient 1
Of all somatic mutations found on sequencing, 63 to 69% were heterogeneous
Intratumor heterogeneity Geringer et al., NEJM 2012
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Phylogenetic relationships of tumor regions
Driver gene
Intratumor heterogeneity Geringer et al., NEJM 2012
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The phenomenon by which some cancers that contain multiple genetic and epigenetic abnormalities remain dependent on (addicted to) one or a few genes for both maintenance of the malignant phenotype and cell survival
Weinstein and Joe, Nature Rev Clin Oncol, 2006
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siRNA mediated specific knockdown of the mutant EGFR allele in NSCLC cells
Sordella et al., Science 2004
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Models of oncogene addictionTorti and Trusolino, 2011
Genetic streamlining Oncogenic shock
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A common signaling cascade may underlie ‘‘addiction’’ to the Src, BCR-ABL, and EGF receptor oncogenes
Sharma et al., Cancer Cell 2006
Pro-apoptotic
Pro-survival
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How can Driver gene / oncogene addiction be identified?
Search for mutations that occur exclusively with known mutations of addicted oncogenes
Search for oncogenes whose inhibition result in induction of apoptosissiRNA screenInhibitor screen
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RNAi screening of the tyrosine kinome identifies therapeutic targets in AML
Tyner et al., Blood, 2008
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CMK cell: JAK3 A572V
HMC1.1 cell: c-KIT (V560G)
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We established a high-throughput platform to profile500 cell lines derived from diverse epithelial cancers for sensitivity to14 kinase inhibitors.
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Profiling of 500 cell lines with a variety of selective kinase inhibitors
Erlotinib(EGFR)
PHA665752(MET)
CL-387,785(EGFR irrev.)
HKI-272(EGFR, HER2)
Sunitinib(PDGFR, FLT-2, c-Kit, VEGFR2)
AZ628(BRAF)
AZD0530(Src family)
Compound 14(Bcr-Abl, Src family)
MK-0457 (Aurola, FLT-3)
Sorafenib (BRAF, c-KIT, FLT-3, PDGFRb)
Imatinib (Bcr-Abl, c-KIT, PDGFR)
NVP-TAE684 (ALK)
PD-173074(FGFR)
PF-2341066(c-MET, ALK)
HER
BRAF
MET
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Kris et al., ASCO 2011
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Kris et al., ASCO 2011
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EGFR
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Phase III trial for patients selected by EGFR mutation (as of ASCO 2012)
Study Race TKI NPFS OS
TKI CTx HR TKI CTx HR
NEJ002 Japanese G 228
10.8 5.4
0.32(0.24– 0.44)
27.7 26.60.88
(0.63-1.24)
WJTOG3405 Japanese G 172 9.6 6.6 052
(038-072) 35.5 38.81.18
(0.77-1.83)
OPTIMAL Chinese E 154
13.7 4.6 0.16
(0.11-0.26) 22.7 28.91.04
(0.69-1.58)
EURTAC Caucasian E 17
3 9.7 5.2 0.37(0.25-0.54) 19.3 19.5
1.04(0.65-1.68)
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Approx. % of patients with PD harboring sensitive EGFR mutation treated with EGFR-
TKI
0mo 3mo 6mo 9mo 12mo0
10
20
30
40
50
60
70
80
90
100
IPASS
NEJ
WJTOG
OPTIMAL
% o
f pati
ents
wit
h P
D
About 20-30% of the patients progressed before 6 months
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Why is response heterogenous?
Mutation classX19del ≥ L858R > G719X >>>> X20 ins = T790M
Amount of T790M allele
FAS, NFkB
BIM
CRKL
Heterogeneity of driver?
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PFS in patients treated with gefitinib in patients with activating EGFR mutation according to presence or absence of T790M as detected Scorpion–Arms
Maheswaran et al., NEJM 2008
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Bivona, et al. Nature, 2011
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BIM Expression in Treatment-Naive Cancers Predicts Responsiveness to Kinase Inhibitors
Faber et al., Cancer Discovery, 2011
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A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to
tyrosine kinase inhibitors in cancerNg et al., Nature Med., 2012
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Amplification of CRKL Induces Transformationand Epidermal Growth Factor Receptor
Inhibitor Resistance in Human Non–SmallCell Lung Cancers
Cheung et al., Cancer Discovery 2011
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KRAS
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KRAS Dependency in KRAS Mutant Lung Adenocarcinoma Cell Lines
Ras dependency indices (RDI) =relative cell densities following K-Ras shRNAs treatment
1
A Gene Expression Signature Associated with ‘‘K-Ras Addiction’’ Reveals Regulators of EMT and Tumor Cell Survival. Singh et al., Cancer Cell 15: 489-500, 2009
KRAS dependent
KRAS independent
KRAS 変異のある肺癌はかならずしも KRAS 経路に addict していない
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Synthetic lethality by siRNA library in KRAS mutated cell linesSTK33 Scholl et al., Cell
Serine threonine kinasemTOR downstream?Non-oncogene
PLK-1 Luo et al., Cell, 2009identified ~50 synthetic lethal genes from 74905 shRNAsAssociated with mitotic functionNon-oncogene
TBK1 Barbie et al., Nature 2009Suppresses IkB, activates NFkBNFkB is associated with cytokine production, proliferation,
survival , angiogenesis, and invasionCdk 4 Puyol et al., Cancer Cell, 2010
Ablation of Cdk4 results in immediate senescenceLung cancer specific
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HER2
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Incidence of HER 2 mutations in lung cancer (compilation of the 14 recent reports)
Tomizawa et al., Lung Cancer 2011
Overall Ethnicity Sex Smoking Histology0
1
2
3
4
2 2.1
3.63.9
2.7
1.5
1 1
0.3
N=3248
Asian
Cauca
sian
Fem
ale
Male
Never
Ever
Aden
o
Other
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Minami et al., Oncogene 2007
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Adenocarcinoma with HER2 mutation (ins 776 YVMA) treated by trastuzumab (anti HER2 Ab) plus vinorelbine
6/3/09 9/2/094/14/093/17/09
trastuzumab
vinorelbine
x5
Tomizawa et al., Lung Cancer 2011
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MET
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Met amplification in lung cancer
Investigator N Met amplification %
EGFR-TKI treated
Engelman 2007 Adeno 18 4 22.2
Bean 2007 Adeno 43 9 20.9
Suda 2010 Adeno(autopsy) 6 3 50.0
Sequist 2011 Adeno 37 2 5.4
EGFR-TKI untreated
Engelman 2007 Adeno 8 0 0.0
Bean 2007 Adeno 62 2 3.2 Beau-Faller
2008 Adeno 49 10 20.4
Cappuzzo 2008 NSCLC 166 12 7.2
Okuda 2008 Adeno 136 6 4.4
Kubo 2008 Adeno 75 2 2.7
Onozato 2009 Adeno 148 2 1.4
Cappuzzo 2009 NSCLC 435 18 4.1
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Molecular predictors of sensitivity to the MET inhibitor (PHA665752) in lung carcinoma cells
Matsubara et al., JTO, 2010
Cell lines sensitivity IC50
Met amp
EGFR amp
HER2
amp
Met mut
EGFR mut
Her2 mut
KRAS mut
sens
itivi
ty
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Activity of crizotinib in a NSCLC patients with de novo MET amplification
Ou et al., JTO, 2011
MET FISH
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ALK
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Waterfall Plot in Profile 1001**
** 早期死亡および未評価の患者を除く (n=106)*** 早期死亡および評価期間不足のため腫瘍評価が得られていなかった症例を含む (n=116)
Objective response details(all evaluable patients)
N=116**
ORR (95% CI) 61% (52, 70)
Median response duration 48 weeks
Median time to response 8 weeks
Disease control rate at 8, 16 weeks
79%, 67%
BOR CR PR SD PD
Bes
t %C
hang
e in
Tar
get L
esio
ns fr
om B
asel
ine
-100.0
-80.0
-60.0
-40.0
-20.0
0.0
20.0
40.0
60.0
80.0
100.0
* ** * * * * * * * * * * *
* : Japanese patient
N N=116***
RR (95% CI) 61% (52 ~ 70)
Median of respose 48w
Median until response 8 w
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Progression-Free Survival (N=119)
Censored
95% Hall-Wellner Band
1.0
0.8
0.6
0.4
0.2
0Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
0 5 10 15 20
Months119 73 29 8 1n at risk
Median PFS = 10.0 months (95% CI: 8.2, 14.7)50 events (42%; 40 PD events) 69 patients (58%) censored, 59/69 (86%) in follow-up for PFS
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EGFR and ALK lung cancer
EGFR ALK
discovery 2004 2007
Clinical backgroundNon-
smoker、 female,ad,Asian
Non-smoker, young
histologyReplacemt growth,
non-mucinousAcinar,cribriform,
signet
Incidence in Ad 40-50% 5-8%
Mechanism of acativation
Deletion~point mutation tramnslocation
TKI gefitinib/ erlotinib crizotinib
RR 60-80% 50-60%
MST 9~10~12 mo 10 month
m
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ROS1
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2
2
2
3
2
1
Variants of ROS fusionTakeuchi et al., Nature Med 2012
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Key results: summary of tumour responses in patients with advanced ROS1+ NSCLC (n=14*)
† ‡
PD SD PR CR100
80
60
40
20
0
–20
–40
–60
–80
–100
16+
15+
18+4+ 12+
8+22+ 18 44+
20+35+ 48+
*Response-evaluable population†Tumour ROS1 FISH-positive, but negative for ROS1 fusion gene expression‡Crizotinib held for >6 wks prior to first scans which showed PD+, treatment ongoing
Dec
reas
e o
r in
crea
se f
rom
bas
elin
e (%
) Shaw et al. J Clin Oncol 30, 2012 (suppl; abstr 7508)
Response rate 8/14 = 57 %
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RET
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Variants of RET fusion
KIF5B RET Ju Kohno Takeuchi
Lipsin Total
K15 R12 1 3 8 8 20
K16 R12 1 1 1 3 6
K22 R12 1 1 2
K23 R12 1 1 1 3
K24 R11 1 1
K15 R11 1 1
K24 R8 1 1
CCDC6 R12 2 2
Takeuchi et al., Nat Med., 2012
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RET lung cancer is sensitive to RET TKI
Lipson et al., 2012
Kohno et al, 2012
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Lung cancer and receptor tyrosine kinases
mutationtranslocationamplification
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Acquired resistance
獲得耐性
مقاومة اكتسبت
획득 내성
获得性耐药
獲得性耐藥 kháng lại
רכשה ההתנגדות
oporność nabyta
erworbene Resistenz
hankitun resistenssin
erhvervet resistens
resistencia adquirida
ความต้�านทานทได้�มาεπίκτητης αντοχής
verworven resistentie
resistenza acquisita
приобретенной устойчивости
acquiritur resistentia
résistance acquise
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Acquired resistance to EGFR-TKI therapy
A: secondary alteration of the target gene
YYT790M
D761YL747ST854A
EGFR-TKI
Kobayashi, NEJM 2005, Pao , PLoS Med 2005Balak, CCR 2006Costa, JCO 2008Bean, CCR 2008
Y
B: activation of other kinases
Y YYYMETamp
Engelman et al., Science 2007Bean et al., PNAS 2007
ATP
IGF1?, HGF?
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Mechanisms of acquired resistance
Unknown Oncogene/ ALK-
9%EGFR mut/ALK-9%
KRAS mut/ALK-9%
KRAS mut/
ALK+*9%
ALK CNG9%
ALK Mutation/CNG9%
ALK Mutation27%
ALK+/Unknown Mechanism*
18%
ResistanceMutation
ALK Copy NumberGain (CNG)
Doebele et al., Clin Can Res 2012
to crizotinib in ALK+ NSCLC
AlternateOncogene
N=37
to EGFR-TKI in EGFR+ NSCLC
Sequist et al., Sci Translational Med., 2012
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Summary…Driver gene mutations in lung cancer
All the driver genes so far identified that addict lung cancer cells are receptor tyrosine kinases activated by mutation (EGFR, HER2, DDR2), amplification (MET, FGFR1) or translocation (ALK, ROS1, RET)
Pharmacologic inhibition of driver gene product typically achieve ~60-70% response rate and ~10 month PFS
There is heterogeneity in response even within patients having driver gene mutation caused by additional alterations
Acquired resistance is inevitable, and its overcoming is of utmost importance.