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Old 04-13-2009, 12:54 PM   #1
Rich66
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Activated PI3K and RTK signaling and response/resistance to HER2 targeted therapy

2009 AACR Annual Meeting
April 18-22, 2009
Denver, CO

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Abstract Number:
765
Session Title:
Predictive Markers for Selecting Therapy
Presentation Title:
Activated PI3K and RTK signaling and response/resistance to HER2 targeted therapy
Presentation Start/End Time:
Sunday, Apr 19, 2009, 8:00 AM -12:00 PM
Location:
Hall B-F, Poster Section 32
Poster Section:
32
Poster Board Number:
24
Poster Rating:
Highly-Rated Poster Presentation
Author Block:

Neil A. O'Brien,
Brigid C. Browne,
Lucy Chow,
Charles Ginther,
Brian Bensadigh,
Mohammad S. Atefi,
Jane Arboleda,
Michael J. Duffy,
John Crown,
Norma O'Donovan,
Dennis J. Slamon. UCLA, Los Angeles, CA, National Institute for Cellular Biotechnology, Dublin, Ireland, UCD School of Medicine and Medical Science, Conway Institute, Dublin, Ireland
Trastuzumab and lapatinib provide clinical benefit to women with HER2 positive breast tumors, however, not all patients whose tumors overexpress HER2 respond. In this study we have developed and characterized cell line models of both clinical forms of resistance to HER2 targeted therapy, i.e., de novo and acquired resistance, and used them to identify the molecular alterations that play a role in response and resistance. Seventeen HER2 positive breast cancer cell lines were tested for response to the HER2 targeted agents, trastuzumab and lapatinib. In vitro responses were measured by two independent assays; cell count and colony formation assay. Tumor xenografts of the cell lines were established and measured for in vivo response to trastuzumab. Acquired resistance was established by culturing BT-474 and SKBR3 cells in high dose trastuzumab (105 mg/ml) for 9 months and characterized for both in vitro and in vivo response to HER2 targeted therapy. Levels of HER2, p-HER2, EGFR, p-EGFR, IGF-1R, p-IGF-1R, p95, PTEN, STMN1 and p27, and the presence of PIK3CA activating mutations were assessed in each cell line and correlated with response data. Analysis of the cell line panel revealed that SUM-225, HCC-1419, HCC-1954, HCC-1569 and JIMT-1 display de novo resistance to trastuzumab. UACC-893, UACC-732, HCC-1569, MDA-MB-361 and JIMT-1 are resistant to lapatinib (IC50 > 1 mM). SUM-225, HCC-1419 and HCC-1954, despite being resistant to trastuzumab are sensitive to lapatinib, whereas HCC-1569 and JIMT-1 are resistant to both trastuzumab and lapatinib. We also find that both BT-474 and SKBR3 trastuzumab conditioned cell lines have significantly reduced response to trastuzumab but remain sensitive to lapatinib. Resistance to trastuzumab correlated significantly with active PI3K signaling (p = 0.003), as assessed by combined analysis of PTEN status and PIK3CA mutation status. However, response to lapatinib did not correlate with increased PI3K activity. Of note, four of the lapatinib sensitive (IC50 < 1 mM) cell lines contain activating mutations of PIK3CA. Response to lapatinib correlated significantly with levels of HER-2 (p = 0.013), pHER-2 (p = 0.086), p95 (p = 0.033), p-EGFR (p = 0.019) and p-IGFR (p = 0.046). We have identified and characterized cell line models of both de novo and acquired resistance to HER2 targeted therapy. Analysis of these models suggests that increased activation of PI3K signaling plays a critical role in resistance to trastuzumab therapy but not lapatinib. High levels of receptor tyrosine kinase signaling may sensitize the HER2 positive cells to lapatinib.
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