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!!!

Maria.Debiec-Rychter@med.kuleuven.be