TY - JOUR
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.
N1 - Publisher Copyright:
©2017 AACR.
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.
AB - 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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U2 - 10.1158/1078-0432.CCR-16-2287
DO - 10.1158/1078-0432.CCR-16-2287
M3 - Article
C2 - 28381415
AN - SCOPUS:85027131060
SN - 1078-0432
VL - 23
SP - 4323
EP - 4334
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -