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Resistance to TK inhibitors: KIT and PDGFRA Maria Debiec-Rychter, M.D., Ph.D. Center for Human Genetics, KULeuven, Belgium ESMO meeting Milan, May 13th,

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Presentation on theme: "Resistance to TK inhibitors: KIT and PDGFRA Maria Debiec-Rychter, M.D., Ph.D. Center for Human Genetics, KULeuven, Belgium ESMO meeting Milan, May 13th,"— Presentation transcript:

1 Resistance to TK inhibitors: KIT and PDGFRA Maria Debiec-Rychter, M.D., Ph.D. Center for Human Genetics, KULeuven, Belgium ESMO meeting Milan, May 13th, 2008

2 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

3 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

4 In vitro studies: primary resistance KIT PDGFRA MM M M MM 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-binding domain

5 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 2003 Heinrich et al., J Clin Oncol, 2006

6 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 9 25% (n=4) 48% (n=23) 35% (n=58) 38% (n=85) No mutation 33% (n=6) 0% (n=9) 25% (n=52) 22% (n=61) Progressivedisease KIT exon 11 4%5%3% 4% KIT exon 9 0%17% 16% No mutation 33%56%19% 25%

7 GIST: KIT and PDGFRA Mutations Predict Event-Free Survival 0100200300400500600700800 0 10 20 30 40 50 60 70 80 90 100 Days Event-free survival (%) 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)

8 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)

9 (years) 012345 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 +/- 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

11 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 2005 Wardelmann et al. Lancet Oncology 2005 Heinrich et al. J Clin Oncol 2007 Desali et al.. Clin Cancer Res 2007

12 Secondary imatinib-resistance KIT mutations in GIST M M Membrane ATP-binding Catalytic domain Juxtamembrane domain Dimerization domain X X Exon 13 & 14 Exon 17 Ligand-binding domain

13 Secondary imatinib-resistance KIT mutations in GISTs

14 Heinrich et al. JCO 2006 Secondary KIT Mutations in GIST Show Varying Intrinsic Resistance to Imatinib

15 Primary and Secondary KIT Mutations in Imatinib- Resistant GIST Show Varying Intrinsic Sensitivity to Alternate TK Inhibitors IC-50 of TK Inhibitors (uM) SunitinibNilotinibSorafenibDasatinibPKC412Imatinib Primary mutation KIT N822Knd3.03.50.86nd>10 PDGFRA D842V>51.30.20.06<0.1>5 Secondary mutation KIT 560Vdel/V654A<0.5<0.21.10.6<0.53.9 KIT 557-8WKdel/T670I<0.5>100.97.5<0.5>10 KIT V559D/D820Ynd<0.30.90.4nd3.2 Debiec-Rychter et al. Gastroenterology 2005 Prenen et al. CCR 2006 Guo et al. CCR 2007

16 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

17 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

18 THANK YOU!!! Maria.Debiec-Rychter@med.kuleuven.be


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