Resistance to TK inhibitors:KIT and PDGFRA
Maria Debiec-Rychter, M.D., Ph.D.
Center for Human Genetics, KULeuven, Belgium
ESMO meetingMilan, May 13th, 2008
Resistance to Imatinib in GISTs
• Primary resistance – <180 days of therapy without initial objective
response• ~10-20% of patients
• Secondary resistance – >180 days of therapy and intial objective
response• Median time to tumor progression: 20-24 months
• 10-20% of patients
• Response to Imatinib relates to mutational profile of the tumor and not to detectable KIT expression
Primary Resistance to Imatinib in GISTs
In vitro studies: primary resistance
KIT PDGFRA
M M
M
M
M M
Sensitivity to imatinib depends on the type and the location of KIT and PDGFRA mutations: some activation loop domain mutations are
intrinsic imatinib-resistant
80-85% 5-10%
Exon 11: 66%
Exon 9: 13%
Exon 17: 0.6%
Exon 13: 1.2%Cytoplasm
M
Exon 12: 1.5%Membrane
Exon 14: 0.3%
Exon 18: 5.6%
Corless et al., J Clin Oncol 2004
Ligand-bindingdomain
Heterogeneous Sensitivity to Imatinib of TK2 Activation Loop Domain Mutations
• Primary Imatinib-sensitive • Del DIMH842-845,
Del I843• D846Y, N848K, Y849K
• Primary Imatinib-resistant – Amino acid substitutions
within codon 842:• D842V (60% of all
PDGFRA mutants)• RD841-842KI• DI842-843IM
• Primary Imatinib-sensitive • N822K• D820Y• Del Q575_P577
• Primary Imatinib-resistant • D816V• D816H• N882H• C809G
KIT exon 17 mutants PDGFRA exon 18 mutants
Heinrich et al., J Clin Oncol, 2003 Heinrich et al., Science 2003Heinrich et al., J Clin Oncol, 2006
Clinical Studies: Relationship Between Kinase Genotype and Response on Imatinib Mesylate Therapy
(1) B2222 Phase II trial: Heinrich et al., J Clin Oncol, 2003 (2) EORTC Phase I/II trial: Debiec-Rychter et al. Eur J Cancer 2004(3) EORTC-AustralAsian Phase III trial: Debiec-Rychter et al. Eur J Cancer 2006
EORTC phase I/II
(n=37)
B2222 phase II (n=127)
EORTC AustralAsian
phase III (n=363)
Overall Average
Objective response
KIT exon 11 83%
(n=24)*83% (n=85)
*70% (n=248)
*74% (n=357)
KIT exon 925% (n=4)
48% (n=23)
35% (n=58)
38% (n=85)
No mutation33% (n=6)
0% (n=9)
25% (n=52)
22% (n=61)
Progressive disease
KIT exon 11 4% 5% 3% 4%
KIT exon 9 0% 17% 17% 16%
No mutation 33% 56% 19% 25%
GIST: KIT and PDGFRA Mutations Predict Event-Free Survival
0 100 200 300 400 500 600 700 8000
102030405060708090
100
Days
Ev
ent-
fre
e s
urv
iva
l (%
)
KIT exon 9 (n=23)
No kinase mutation(n=9)
KIT exon 11 (n=85)
Heinrich et al. J Clin Oncol. 2003;21:4342.
B2222 Phase II trial KIT exon 11 vs exon 9 (P<0.0001) KIT exon 11 vs no mutation (P<0.0001) KIT exon 9 vs no mutation (P=0.1428)
(years)
0 1 2 3 4
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : 37 52 27 14 2
47 58 29 12 0
135 248 207 120 33
Wild
Kit-ex9
Kit-ex11
Progression free survival
GIST: KIT and PDGFRA Mutations Predict Event-Free Survival
Debiec-Rychter et al. Eur J Cancer 2006
Phase III Study (EORTC 62005)
KIT exon 11 (n=248)
KIT exon 9 (n=58) No kinase mutation(n=52)
(years)
0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Progression free survival
Median PFS (months) 6 / 19
3 years estimate (%) 5 / 17
P-value (logrank test) 0.017
KIT exon 9 mutants
KIT exon 9 mutants: 400 mg / 800 mg - Other patients: 400 mg / 800 mg
MetaGIST project, ASCO, June 2007
Dose Dependence of KIT Exon 9 Mutants
+/- 10-20% of patients
Relates to the mutational profile of the tumor:
– ~30% KIT exon 9 (dose dependent)– PDGFRA D842V mutant – Majority of Wild-Type GISTs:
• Pediatric GISTs (Carney Triad)• Carney-Stratiakis dyad• NF1 GISTs• Adult Wild-Type GISTs
Clinical Studies: Primary Resistance to Imatinib
Secondary Resistance
– secondary mutation in KIT or PDGFRA resulting in strong phosphorylation: new mutations may differ within given nodule and in various metastatic sites! Majority of cases: ~80%
– genomic amplification and overexpression of KIT/PDGFRA without new point mutations
– loss of KIT expression, accompanied by activation of an alternative tyrosine kinase or or other (onco)gene(?)
Debiec-Rychter et al. Gastroeneterology 2005Wardelmann et al. Lancet Oncology 2005Heinrich et al. J Clin Oncol 2007Desali et al.. Clin Cancer Res 2007
Secondary imatinib-resistance KIT mutations
in GIST
M
M
Membrane
ATP-binding
Catalytic domain
Juxtamembrane domain
Dimerization domainXX
Exon 13 & 14
Exon 17
Ligand-binding domain
Secondary imatinib-resistance KIT mutations in GISTs
Heinrich et al. JCO 2006
Secondary KIT Mutations in GIST Show Varying Intrinsic Resistance to Imatinib
Primary and Secondary KIT Mutations in Imatinib-Resistant GIST Show Varying Intrinsic Sensitivity to
Alternate TK Inhibitors
IC-50 of TK Inhibitors (uM)
Sunitinib Nilotinib Sorafenib Dasatinib PKC412 Imatinib
Primary mutation
KIT N822K nd 3.0 3.5 0.86 nd >10
PDGFRA D842V >5 1.3 0.2 0.06 <0.1 >5
Secondary mutation
KIT 560Vdel/V654A <0.5 <0.2 1.1 0.6 <0.5 3.9
KIT 557-8WKdel/T670I <0.5 >10 0.9 7.5 <0.5 >10
KIT V559D/D820Y nd <0.3 0.9 0.4 nd 3.2
Debiec-Rychter et al. Gastroenterology 2005Prenen et al. CCR 2006Guo et al. CCR 2007
Heterogeneity of Imatinib-Resistant Mutations in GISTs
KIT D560V
KIT D560V /V654A
KIT D560V /T670I
KIT D560V /D820Y
KIT D560V /V654A
KIT D560V /D823Y
None of the second-line TK inhibitor is effective against all imatinib-resistant mutations
Strategies to overcome the problem of heterogeneous imatinib-resistant mutations in
GISTs
• To enhance the cellular degradation of constitutively activated KIT and PDGFRA oncoproteins
• To inhibit KIT or PDGFRA receptor and signaling pathways proteins that utilise shared signalling pathways with KIT/PDGFRA
• PI3K/AKT
• RAS/RAF/MAPK
• PKC
THANK YOU!!!