HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2

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Hanker , A B , Garrett , J T , Estrada , M V , Moore , P D , Ericsson , P G , Koch , J P , Langley , E , Singh , S , Kim , P S , Frampton , G M , Sanford , E , Owens , P , Becker , J , Groseclose , M R , Castellino , S , Joensuu , H , Huober , J , Brase , J C , Majjaj , S , Brohee , S , Venet , D , Brown , D , Baselga , J , Piccart , M , Sotiriou , C & Arteaga , C L 2017 , ' HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2 ' , Clinical Cancer Research , vol. 23 , no. 15 , pp. 4323-4334 . https://doi.org/10.1158/1078-0432.CCR-16-2287

Title: HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2
Author: Hanker, Ariella B.; Garrett, Joan T.; Estrada, Monica Valeria; Moore, Preston D.; Ericsson, Paula Gonzalez; Koch, James P.; Langley, Emma; Singh, Sharat; Kim, Phillip S.; Frampton, Garrett M.; Sanford, Eric; Owens, Philip; Becker, Jennifer; Groseclose, M. Reid; Castellino, Stephen; Joensuu, Heikki; Huober, Jens; Brase, Jan C.; Majjaj, Samira; Brohee, Sylvain; Venet, David; Brown, David; Baselga, Jose; Piccart, Martine; Sotiriou, Christos; Arteaga, Carlos L.
Contributor: University of Helsinki, Clinicum
Date: 2017-08-01
Language: eng
Number of pages: 12
Belongs to series: Clinical Cancer Research
ISSN: 1078-0432
URI: http://hdl.handle.net/10138/297912
Abstract: Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2(+)) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab. Experimental Design: HER2(+) BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples. Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2(+) early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2(+) early breast cancer treated with neoadjuvant anti-HER2 therapy. Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. (C) 2017 AACR.
Subject: KINASE INHIBITOR LAPATINIB
CCND1 AMPLIFICATION
ACQUIRED-RESISTANCE
ERBB RECEPTORS
SOLID TUMORS
OPEN-LABEL
GROWTH
TRASTUZUMAB
ONCOGENE
CELLS
3122 Cancers
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