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HER2-Overexpressing Breast Cancers Amplify FGFR Signaling Upon Acquisition Of

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HER2-Overexpressing Breast Cancers Amplify FGFR Signaling Upon Acquisition Of Author Manuscript Published OnlineFirst on April 5, 2017; DOI: 10.1158/1078-0432.CCR-16-2287 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 Title: HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of 3 resistance to dual therapeutic blockade of HER2 4 Authors: Ariella B. Hanker*1,2, Joan T. Garrett*1,3, Mónica Valeria Estrada2, Preston D. 5 Moore1, Paula González Ericsson2, James P. Koch1, Emma Langley4, Sharat Singh4, Phillip S. 6 Kim4, Garrett M. Frampton5, Eric Sanford5, Philip Owens6, Jennifer Becker1, M. Reid 7 Groseclose7, Stephen Castellino7, Heikki Joensuu8, Jens Huober9, Jan C. Brase10, Samira 8 Majjaj11, Sylvain Brohée11, David Venet11, David Brown11, José Baselga12, Martine Piccart11, 9 Christos Sotiriou11 and Carlos L. Arteaga1,2,6 10 Affiliations: 11 1Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, 12 TN, USA 13 2Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville 14 TN, USA 15 3Current address: Division of Pharmaceutical Sciences, University of Cincinnati College of 16 Pharmacy, Cincinnati, OH, USA 17 4Prometheus Laboratories, San Diego, CA, USA 18 5Foundation Medicine, Cambridge, MA, USA 19 6Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA 20 7Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle 21 Park, NC, USA 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2017; DOI: 10.1158/1078-0432.CCR-16-2287 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 22 8Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland 23 9Department of Gynecology, University of Ulm, Ulm, Germany 24 10Novartis Pharmaceuticals, Basel, Switzerland 25 11Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium 26 12Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 27 *These authors contributed equally. 28 Running Title: FGFR signaling promotes resistance to dual HER2 blockade. 29 Keywords: HER2, FGFR, trastuzumab, drug resistance, breast cancer 30 Financial Support: This work was supported by American Cancer Society 118813-PF-10-070- 31 01-TBG (JTG) and Department of Defense BC093376 (JTG) Postdoctoral Fellowship Awards; 32 Department of Defense Postdoctoral Fellowship Award BC103785 (ABH); NIH/NCI K12 33 Award CA090625 (ABH); NCI R01 grant CA080195 (CLA); NIH Breast Cancer Specialized 34 Program of Research Excellence (SPORE) grant P50 CA98131; and Vanderbilt-Ingram Cancer 35 Center Support Grant P30 CA68485. 36 Corresponding author: Carlos L. Arteaga, Vanderbilt University Medical Center, 2220 Pierce 37 Ave, 777 PRB, Nashville, TN 37232-6307. Phone: 615-936-0975; Fax: 615-343-7602; E-mail: 38 [email protected] 39 Conflict of interest statement: The authors have no competing financial interests. 40 Word count (excluding abstract, references, and figure legends): 5,223 41 Total number of figures: 6 42 2 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2017; DOI: 10.1158/1078-0432.CCR-16-2287 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 43 Statement of Translational Relevance 44 Dual blockade of HER2, with the combinations of trastuzumab and lapatinib or trastuzumab and 45 pertuzumab, has been shown to be superior to trastuzumab alone. However, acquired resistance 46 to anti-HER2 therapies remains a problem. We found an increase in FGF3/4/19 gene copy 47 number in HER2-overexpressing xenografts with acquired resistance to lapatinib + trastuzumab. 48 This was accompanied by an increase in FGFR phosphorylation, reduced levels of lapatinib in 49 drug-resistant tumors, and changes in the tumor microenvironment. Combining FGFR inhibitors 50 with lapatinib + trastuzumab led to regression of the drug-resistant tumors. Finally, high FGFR1 51 gene expression and amplification of FGFR1 and FGF3 correlated with an inferior clinical 52 response to anti-HER2 therapies in patients with early HER2+ breast cancer. These findings 53 support profiling genes in the FGFR pathway in tumors with acquired resistance to HER2- 54 directed therapies and the clinical investigation of FGFR and HER2 inhibitors in these treatment- 55 refractory HER2+ breast cancers. 56 3 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2017; DOI: 10.1158/1078-0432.CCR-16-2287 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 57 Abstract (245/250 words): 58 Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown 59 to be superior to single-agent trastuzumab. However, a significant fraction of HER2- 60 overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we 61 sought to discover the mechanisms of acquired resistance to the combination of lapatinib + 62 trastuzumab. 63 Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab 64 long-term until resistance developed. Potential mechanisms of acquired resistance were 65 evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation 66 sequencing. In vitro experiments were performed to corroborate these findings and a novel drug 67 combination was tested against LTR xenografts. Gene expression and copy number analyses 68 were performed to corroborate our findings in clinical samples. 69 Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an 70 increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and 71 reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to 72 lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these 73 changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 74 correlated with a statistically shorter progression-free survival in patients with HER2+ early 75 breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene 76 amplification correlated with a lower pathological complete response in patients with HER2+ 77 early breast cancer treated with neoadjuvant anti-HER2 therapy. 78 Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which 79 can be diminished by the combination of HER2 and FGFR inhibitors. 4 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2017; DOI: 10.1158/1078-0432.CCR-16-2287 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 80 Introduction 81 Approximately 20% of breast cancers harbor gene amplification of the receptor tyrosine kinase 82 (RTK) HER2 (ERBB2) (1). HER2 is a member of the ERBB family of trans-membrane RTKs. 83 Upon ligand-induced dimerization, ERBB family receptors undergo conformational changes that 84 trigger kinase activation and subsequent signal transduction through oncogenic pathways, such 85 as phosphoinositide 3-kinase (PI3K)-Akt and RAS/RAF/MEK/ERK. Anti-HER2 therapies 86 include trastuzumab (T), a humanized monoclonal antibody directed against the ectodomain of 87 HER2; pertuzumab, an antibody that blocks dimerization of HER2 with other ERBB receptors; 88 lapatinib (L), a reversible, ATP-competitive tyrosine kinase inhibitor (TKI) of HER2 and EGFR 89 (2); and trastuzumab-DM1, a conjugate of trastuzumab linked to the chemotherapeutic 90 maytansine. Recent clinical studies have shown that dual inhibition of HER2, such as the 91 combination of L + T or T + pertuzumab, is more effective than trastuzumab (3-5). Despite these 92 advances, resistance to dual HER2 blockade still occurs in patients with HER2+ breast cancer. 93 The mechanisms of acquired resistance to dual HER2 inhibition remain to be fully explored. 94 Proposed mechanisms of resistance to HER2 inhibitors include the presence of truncated HER2, 95 bypass signaling by other ERBB receptors or other RTKs, activation of compensatory survival 96 pathways, defects in apoptosis and cell cycle control, and mutational activation of the PI3K 97 pathway [reviewed in (2)]. We and others have previously shown that activating PIK3CA 98 mutations can promote resistance to dual inhibition of HER2 (6-8). 99 In order to discover novel mechanisms of resistance to dual HER2 blockade, we generated 100 HER2-amplified BT474 xenografts resistant to the combination of L + T. We found increased 101 copy number of the FGF3, FGF4, and FGF19 genes in L + T-resistant (LTR) tumors. The 102 FGF3/4/19 genes reside on chromosome 11q13, a region which also harbors CCND1, and is 5 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2017; DOI: 10.1158/1078-0432.CCR-16-2287 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 103 amplified in ~15% of breast
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