HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2

Ariella B. Hanker, Joan T. Garrett, Monica Valeria Estrada, Preston D. Moore, Paula Gonzalez 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 BroheeDavid Venet, David Brown, Jose Baselga, Martine Piccart, Christos Sotiriou, Carlos L. Arteaga

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4323-4334
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Breast Neoplasms
Therapeutics
Drug Combinations
Heterografts
Trastuzumab
lapatinib
Neoplasms
Tumor Microenvironment
Gene Dosage
Gene Amplification
Protein-Tyrosine Kinases
Disease-Free Survival
Research Design
Phosphorylation
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2. / 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.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4323-4334.

Research output: Contribution to journalArticle

Hanker, AB, Garrett, JT, Estrada, MV, Moore, PD, Ericsson, PG, Koch, JP, Langley, E, Singh, S, Kim, PS, Frampton, GM, Sanford, E, Owens, P, Becker, J, Groseclose, MR, Castellino, S, Joensuu, H, Huober, J, Brase, JC, Majjaj, S, Brohee, S, Venet, D, Brown, D, Baselga, J, Piccart, M, Sotiriou, C & Arteaga, CL 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
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. / HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4323-4334.
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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.",
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T1 - HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2

AU - Hanker, Ariella B.

AU - Garrett, Joan T.

AU - Estrada, Monica Valeria

AU - Moore, Preston D.

AU - Ericsson, Paula Gonzalez

AU - Koch, James P.

AU - Langley, Emma

AU - Singh, Sharat

AU - Kim, Phillip S.

AU - Frampton, Garrett M.

AU - Sanford, Eric

AU - Owens, Philip

AU - Becker, Jennifer

AU - Groseclose, M. Reid

AU - Castellino, Stephen

AU - Joensuu, Heikki

AU - Huober, Jens

AU - Brase, Jan C.

AU - Majjaj, Samira

AU - Brohee, Sylvain

AU - Venet, David

AU - Brown, David

AU - Baselga, Jose

AU - Piccart, Martine

AU - Sotiriou, Christos

AU - Arteaga, Carlos L.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

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