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Resistance to TK inhibitors: KIT and PDGFRA

Resistance to TK inhibitors: KIT and PDGFRA. Maria Debiec-Rychter , M.D., Ph.D. Center for Human Genetics, KULeuven, Belgium ESMO meeting Milan, May 1 3 th, 2008. Resistance to Imatinib in GISTs. Primary resistance <180 days of therapy without initial objective response

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Resistance to TK inhibitors: KIT and PDGFRA

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  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. Primary Resistance to Imatinib in GISTs • 10-20% of patients • Response to Imatinib relates to mutational profile of the tumor and not to detectable KIT expression

  4. In vitro studies: primary resistance 5-10% 80-85% PDGFRA Ligand-binding domain KIT Exon 9: 13% M Membrane Exon 12: 1.5% Exon 11: 66% M M Exon 14: 0.3% M Exon 13: 1.2% M Cytoplasm Exon 18: 5.6% Exon 17:0.6% 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 Corless et al., J Clin Oncol 2004

  5. Primary Imatinib-sensitive N822K D820Y Del Q575_P577 Primary Imatinib-resistant D816V D816H N882H C809G Heterogeneous Sensitivity to Imatinib of TK2 Activation Loop Domain Mutations KIT exon 17 mutants PDGFRA exon 18 mutants • 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 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 Responseon Imatinib Mesylate Therapy (1) B2222 Phase II trial: Heinrich et al., J Clin Oncol, 2003 (2) EORTCPhase 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

  7. GIST: KIT and PDGFRA Mutations Predict Event-Free Survival • 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) B2222 Phase II trial 100 90 KIT exon 11 (n=85) 80 70 60 KIT exon 9 (n=23) 50 Event-free survival (%) 40 30 20 No kinase mutation (n=9) 10 0 0 100 200 300 400 500 600 700 800 Days Heinrich et al. J Clin Oncol. 2003;21:4342.

  8. GIST: KIT and PDGFRA Mutations Predict Event-Free Survival Phase III Study (EORTC 62005) KIT exon 11 (n=248) KIT exon 9 (n=58) No kinase mutation (n=52) Debiec-Rychter et al. Eur J Cancer 2006

  9. Dose Dependence of KIT Exon 9 Mutants 100 KIT exon 9 mutants 90 80 70 60 50 Progression free survival 40 30 20 10 0 0 1 2 3 4 5 (years) KIT exon 9 mutants: 400 mg / 800 mg - Other patients: 400 mg / 800 mg MetaGIST project, ASCO, June 2007

  10. Clinical Studies: Primary Resistance to Imatinib +/- 10-20% of patients Relates to the mutational profile of the tumor: • ~30%KIT exon 9 (dose dependent) • PDGFRAD842V mutant • Majority of Wild-Type GISTs: • Pediatric GISTs (Carney Triad) • Carney-Stratiakis dyad • NF1 GISTs • Adult Wild-Type GISTs

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

  13. Secondary imatinib-resistance KIT mutations in GISTs

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

  15. Primary and Secondary KIT Mutations in Imatinib-Resistant GIST Show Varying Intrinsic Sensitivity to Alternate TK Inhibitors 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 / T670I KIT D560V KIT D560V / D820Y KIT D560V / V654A KIT D560V / D823Y KIT D560V / V654A 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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