Cyclin E amplification, a novel mechanism of resistance to trastuzumab in HER2 amplified breast cancer Sunday, Apr 18, 2010, 2:25 PM - 2:40 PM
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1 Abstract Print View Page 1 of 1 Presentation Abstract Abstract Number: Presentation Title: Presentation Time: Location: Author Block: 22 Cyclin E amplification, a novel mechanism of resistance to trastuzumab in HER2 amplified breast cancer Sunday, Apr 18, 2010, 2:25 PM - 2:40 PM Room 103, Washington Convention Center Maurizio Scaltriti 1, Pieter Eichhorn 1, Magui Gili 1, Marta Guzman 1, Claudia Aura 1, José Jimenez 1, Ludmila Prudkin 1, Simon R. Green 2, Javier Cortés 1, Sarat Chandarlapaty 3, Sabine Mai 4, Clifford A. Hudis 3, Neal Rosen 3, José Baselga 1. 1 Vall d'hebron Univ. Hospital, Barcelona, Spain; 2 Cyclacel, Dundee, United Kingdom; 3 Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Manitoba Institute of Cell Biology, Winnipeg, MB, Canada Abstract Body: HER2 amplification/overexpression occurs in 20% of breast cancers and is associated with poor prognosis. Therapeutic agents against HER2, including monoclonal antibodies and tyrosine kinase inhibitors, have shown to improve the survival of these patients. However, primary and acquired resistance to these agents is a major barrier to the effective treatment of this disease. Aiming to identify the molecular pathways responsible for resistance to anti-her2 therapy we have established HER2 positive breast cancer cell lines refractory to the anti-proliferative effects of the therapeutic antibody trastuzumab. We have studied their acquired genetic aberrations by performing gene expression microarray and genome single nucleotide polymorphisms analyses. In trastuzumab resistant cells we identified an increase in copy number variation in locus 19q12. This chromosome region comprises seven genes, among them cyclin E1 (CCNE1). We further confirmed Cyclin E over-expression in trastuzumab resistant cells by western blot. To test the hypothesis that increased cyclin E expression could play a role in the acquisition of trastuzumab resistance we have demonstrated that ablation of cyclin E expression by sirna restores trastuzumab sensitivity in HER2 positive resistant cells. Furthermore, we have determined that trastuzumab resistant cells are highly sensitive to the specific CDK inhibitor seliciclib and its more potent derivative Cmpd. 5 (Cyclacel) both in vitro and in vivo. In addition, we have analyzed a cohort of HER2 positive breast cancer patients treated with trastuzumabbased therapy and identified a proportion of patients refractory to trastuzumab that harbor amplification of the cyclin E gene. Our results suggest that cyclin E amplification decreases trastuzumab sensitivity and may provide the rationale to test the efficacy of CDK2 inhibitors in breast cancer patients with cyclin E amplification that escaped trastuzumab therapy. American Association for Cancer Research 615 Chestnut St. 17th Floor Philadelphia, PA 19106
2 Cyclin E amplification, a novel mechanism of resistance to trastuzumab in HER2 amplified breast cancer Maurizio Scaltriti, PhD Experimental Therapeutics Program Vall d Hebron Institute of Oncology Barcelona, Spain
3 Disclosures: Nothing to disclose
4 Mechanisms of trastuzumab activity Other HERs Ligands HER2 Immune Response (ADCC) -Trastuzumab Proliferation RAS/RAF/MEK/ERK Cell Cycle, Survival PI3K/AKT/mTOR p27
5 Mechanisms of resistance to trastuzumab Confirmed mechanisms in the clinic Hyperactivation of the PI3K Pathway Nagata et al, 2004 Cancer Cell Berns et al, 2007 Cancer Cell Eichhorn et al, 2008 Cancer Res Presence of truncated forms of HER2 (p95her2) Scaltriti et al, 2007 JNCI Loss of HER2 expression Mittendorf et al, 2009 Clin Cancer Res
6 Selection of trastuzumab resistant (R) cells R do not respond to the antiproliferative effects of trastuzumab in vitro Relative Proliferation Trastuzumab (nm)
7 Selection of trastuzumab resistant (R) cells R do not respond to the antiproliferative effects of trastuzumab in vitro Relative Proliferation Trastuzumab 18 months Trastuzumab (nm)
8 Selection of trastuzumab resistant (R) cells R do not respond to the antiproliferative effects of trastuzumab in vitro Relative Proliferation Trastuzumab 18 months Relative Proliferation R Trastuzumab (nm) Trastuzumab (nm) (IC50>1uM)
9 Characterization of R cells R cells do not exhibit previously known mechanisms of trastuzumab resistance R R Tras (100nM) pher2 HER2 pigfr IGFR pakt Akt Percentage of cells R G1 S G2 pmapk 50 MAPK Cyclin D Tras (nm) p27 actin
10 Characterization of R cells R cells do not exhibit previously known mechanisms of trastuzumab resistance R R Tras (100nM) pher2 HER2 pigfr IGFR pakt Akt Percentage of cells R G1 S G2 pmapk 50 MAPK Cyclin D Tras (nm) p27 actin
11 Characterization of R cells R cells do not exhibit previously known mechanisms of trastuzumab resistance R R Tras (100nM) pher2 HER2 pigfr IGFR pakt Akt Percentage of cells R G1 S G2 pmapk 50 MAPK Cyclin D Tras (nm) p27 actin
12 Characterization of R cells R cells do not exhibit previously known mechanisms of trastuzumab resistance R R Tras (100nM) pher2 HER2 pigfr IGFR pakt Akt Percentage of cells R G1 S G2 pmapk 50 MAPK Cyclin D Tras (nm) p27 actin
13 Characterization of R cells R cells do not exhibit previously known mechanisms of trastuzumab resistance R R Tras (100nM) pher2 HER2 pigfr IGFR pakt Akt Percentage of cells R G1 S G2 pmapk 50 MAPK Cyclin D Tras (nm) p27 actin
14 Characterization of R cells R cells present cyclin E amplification and overexpression CNV1 CNV2 CNV1 (Chr.19) UQCRFS1 POP4 PLEKHF1 C19orf12 CCNE1 C19orf2 ZNF536 CNV2 (Chr.14) GPR65 GALC R R Tras (100nM) Cyclin E R MKN7 prb(s780) RB p27 actin IHC: Cyclin E
15 Cyclin E/CDK2 addiction of R cells Cyclin E expression modulates trastuzumab sensitivity Knockdown Relative ABS 570nm sicontrol Overexpression Relative ABS 570nm sicontrol + Tras siccne1 siccne1 + Tras control Tras 100nM R R R CE1 CE2 Cyclin E tubulin siccne1 IP:Cyclin E WB:Cyclin E 0 CE1 CE2
16 Cyclin E/CDK2 addiction of R cells CDK2 inhibition decreases proliferation of R cells CDK2 inhibitor: Cmpd 5 (Cyclacel) is trisubstituted purine derivative of seliciclib. IC50 300nM Absorbance at 570nM BT-474 BT-474R Absorbance at 570nM Cmpd5 Ratio to CDK2 CDK CDK CDK CDK LKB CDK CDK BT-474 CLK BT CE CLK CDK control Tras Cdk2i T+C control Tras Cdk2i T+C
17 Cyclin E/CDK2 addiction of R cells CDK2 inhibition leads to G1 arrest and increases cell death of R cells Percentage of cells R G1 S G2 Tras 10 nm Cdk2i 300 nm % Cells % Cells Sub G Annexin V R Tras(100nM) Cdk2i(300nM) R Tras(100nM) Cdk2i(300nM)
18 Cyclin E/CDK2 addiction of R cells CDK2 inhibition decreases prb and promotes cleavage of Parp R Tras(100nM) Cdk2i(300nM) pher2 HER2 prb(s807) prb(s780) Rb cleaved Parp p27
19 Cyclin E/CDK2 addiction of R cells CDK2 inhibition reduces tumor growth of R-derived xenografts
20 Cyclin E amplification/overexpression in HER2+ patients Cyclin E positive: FISH ratio 1.5 and IHC nuclear staining 30 H-Score Patient 1: CCNE1 WT CCNE1 probe DAPI Patient 2: CCNE1 Amp
21 Cyclin E amplification/overexpression in HER2+ patients and resistance to trastuzumab Cohort of patients with cyclin E + (n=16) Metastatic HER2 + breast cancer Cyclin E amplification/overexpression Treated with 1 st -line trastuzumab-containing therapy Compared to similar cohort of patients cyclin E (n=8) No ciclin E (n=8) Blue: no cyclin E amplif/nuclear staining Green: High cyclin ciclin E amplif/nuclear E (n=13) staining PFS probability Median PFS: 4 months vs 13 months P value.046* 4 m 13 m *Breslow test Months
22 Cyclin E amplification/overexpression in HER2+ patients and resistance to trastuzumab Clinical benefit rate Patients (%) No cyclin E High cyclin E!" * nuclear staining 30 H score. P value.030 Clinical benefit rate: CR+PR+SD>6 months.
23 Conclusions cells with acquired resistance to trastuzumab present amplification and overexpression of cyclin E Cyclin E overexpression modulates sensitivity to trastuzumab R cells are addicted to cyclin E-dependent CDK2 activity Amplification/overexpression (nuclear staining) of cyclin E correlates with lower therapeutic response to trastuzumab-based therapy CDK2 inhibition could be a valid strategy to target cyclin E amplified/overexpressing HER2 positive breast cancer
24 Acknowledgments
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