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

Ariella B Hanker, Joan T Garrett, Mónica Valeria Estrada, Preston D Moore, Paula González Ericsson, James P Koch, Emma Langley, Sharat Singh, Phillip S Kim, Garrett M Frampton, Eric Sanford, Philip Owens, Jennifer Becker, M Reid Groseclose, Stephen Castellino, Heikki Joensuu, Jens Huober, Jan C Brase, Samira Majjaj, Sylvain Brohée, David Venet, David Brown, José Baselga, Martine Piccart, Christos Sotiriou & Carlos L Arteaga

abstract 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. 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. 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. LTR tumors exhibited an increase in 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 Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of correlated with a statistically shorter progression-free survival in patients with HER2 early breast cancer treated with adjuvant trastuzumab. Finally, and/or gene amplification correlated with a lower pathologic complete response in patients with HER2 early breast cancer treated with neoadjuvant anti-HER2 therapy. Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. .
   
citation 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, Brohée S, Venet D, Brown D, Baselga J, Piccart M, Sotiriou C, Arteaga C L. HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2. Clin Cancer Res 2017; 23:4323-4334.
   
type journal paper/review (English)
date of publishing 05-04-2017
journal title Clin Cancer Res (23/15)
ISSN electronic 1557-3265
pages 4323-4334
PubMed 28381415
DOI 10.1158/1078-0432.CCR-16-2287