Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer

Luigi Formisano, Yao Lu, Alberto Servetto, Ariella B. Hanker, Valerie M. Jansen, Joshua A. Bauer, Dhivya R. Sudhan, Angel L. Guerrero-Zotano, Sarah Croessmann, Yan Guo, Paula Gonzalez Ericsson, Kyung min Lee, Mellissa J. Nixon, Luis J. Schwarz, Melinda E. Sanders, Teresa C. Dugger, Marcelo Rocha Cruz, Amir Behdad, Massimo Cristofanilli, Aditya BardiaJoyce O’Shaughnessy, Rebecca J. Nagy, Richard B. Lanman, Nadia Solovieff, Wei He, Michelle Miller, Fei Su, Yu Shyr, Ingrid A. Mayer, Justin M. Balko, Carlos L. Arteaga

研究成果: Article

17 引文 斯高帕斯(Scopus)

摘要

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.

原文English
文章編號1373
期刊Nature communications
10
發行號1
DOIs
出版狀態Published - 2019 十二月 1

    指紋

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

引用此

Formisano, L., Lu, Y., Servetto, A., Hanker, A. B., Jansen, V. M., Bauer, J. A., Sudhan, D. R., Guerrero-Zotano, A. L., Croessmann, S., Guo, Y., Ericsson, P. G., Lee, K. M., Nixon, M. J., Schwarz, L. J., Sanders, M. E., Dugger, T. C., Cruz, M. R., Behdad, A., Cristofanilli, M., ... Arteaga, C. L. (2019). Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nature communications, 10(1), [1373]. https://doi.org/10.1038/s41467-019-09068-2