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IMiDs Mechanism of Action and Future Applications. A. Keith Stewart Mayo Clinic in Arizona. Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. IMiD Structures. Side effects. Potency. Potency. Identification of a Primary Target of Thalidomide Teratogenicity.

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imids mechanism of action and future applications

IMiDs Mechanism of Action and Future Applications

A. Keith Stewart Mayo Clinic in Arizona

Scottsdale, Arizona

Rochester, Minnesota

Jacksonville, Florida

imid structures
IMiD Structures

Side effects

Potency

Potency

slide3

Identification of a Primary Target of Thalidomide Teratogenicity

  • Half a century ago, thalidomide was found to be teratogenic, causing multiple birth defects . . . here, we identified cereblon (CRBN) as a thalidomide-binding protein
  • CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth
  • Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity

Takumi Ito, Hideki Ando, Takayuki Suzuki, Toshihiko Ogura, KentaroHotta, Yoshimasa Imamura, Yuki Yamaguchi, Hiroshi Handa. Science. 2010;327:1345-50.

slide4

Cereblon

  • Cereblon on chromosome 3 was first described as associated with human intelligence (Cerebral protein with Lon protease)
  • Functions in the brain as an ionic channel regulator
  • Highly conserved from plants to humans, broadly expressed
  • Regulates AMP kinase in insulin resistance, obesity
  • Forms an E3ligase complex with DDB1, Cul4A, Roc1
slide6

Lenalidomide Resistant MM Cells Lack Cereblon

MM1.S

MM1.S res

CRBN

b-actin

Zhu YX, et al. Blood. 2011;118:4771-9.

slide7

Gene Expression Levels of Cereblon Predict Response Rate to Pomalidomide

33%

19%

CRBN expression as a percentage of the mean levels in all MM

0%

N =

Schuster SR,et al. Leuk Res. Jan 2014; 38(1):23-28

slide8

Gene Expression Levels of CereblonPredict Overall Survival of Pomalidomide Treated Patients

P=0.01

P=0.005

9.1 vs 27 months

Schuster SR,et al. Leuk Res. Jan 2014; 38(1):23-28

slide9

CRBN Binding Proteins Altered by Lenalidomide

Zhu et al. Blood. 2014 Jun 9. [Epub ahead of print]

slide10

CRBN Binding Proteins Altered by Lenalidomide

Zhu et al. Blood. 2014 Jun 9. [Epub ahead of print]

slide11

CRBN Binding Proteins Altered by Lenalidomide

Zhu et al. Blood. 2014 Jun 9. [Epub ahead of print]

slide12

IKZF1/IRF4/MycDegradation After Lenalidomide

Time 3h 6h 24h 48h

Len - + - + - + - +

IKZF1

IKZF3

IRF4

MYC

b-actin

slide16

Sensitivity of MM to Lenalidomide is Correlated with IKAROS Degradation Efficiency

Most resistant cell lines

Most Sensitive cell lines

  • MM cell lines with adenoviral vector expressing IKAROS 1 - luciferase fusion gene. Luciferase activity was measured and normalized to cells treated with DMSO
slide17

CRBN/IZKF1/IRF4 Expression and Drug Resistance

Len Sensitive

Len Resistant

XG1 MM1.S KMS11 H929 JJN3 EJM OCI-MY5 FR4 SKMM

IZKF1

IZKF3

CRBN

IRF4

b-actin

IZKF1 L208R substitution and codon deletion mutation

t(6;14) IgH-IRF4 translocation

Zhu et al. Blood. 2014 Jun 9. [Epub ahead of print]

slide18

Survival after Pomalidomide/Dexamethasone

Zhu et al. Blood. 2014 Jun 9. [Epub ahead of print]

slide19

IkarosExpression and Pomalidomide/Dexamethasone

Overall survival 7.3 vs 27.2 months p=0.004

Lowest Quartile 0/11 Patients Responded

Zhu et al. Blood. 2014 Jun 9. [Epub ahead of print]

slide20

77 gene panel IKZF3 (Aiolis) Mutation: Patient

Progressing on Pomalidomide and Dexamethasone

Tumor, 702 X, 171 mutation reads (24%)

  • IKZF3 point mutation (p.Gly157Arg)
  • exonic, missense, damaging

Germline, 462 X, 0 mutation reads

summary
Summary
  • Cereblonis the IMiD target and accumulates with IMiDbinding
  • Ikarosis rapidly degraded in presence of IMiD and blocked by bortezomib or carfilzomib in vitro
  • Low Cereblonand Ikaroslevels may predict response and survival
  • Resistance can be explained in many cases by disruption of this pathway