Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

Abstract

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Establishment of orthotopic HER2-positive BCBM PDXs.
Figure 2: Differential responses of HER2-positive BCBM PDXs to the combination of BKM120 and RAD001.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. 1

    Wikman, H. et al. Breast Cancer Res. 14, R49 (2012).

    CAS  Article  PubMed Central  Google Scholar 

  2. 2

    Zhang, L. et al. Nature 527, 100–104 (2015).

    CAS  Article  PubMed Central  Google Scholar 

  3. 3

    Filbin, M.G. et al. Nat. Med. 19, 1518–1523 (2013).

    Article  Google Scholar 

  4. 4

    Maire, C.L. et al. Stem Cells 32, 313–326 (2014).

    CAS  Article  PubMed Central  Google Scholar 

  5. 5

    Thorpe, L.M., Yuzugullu, H. & Zhao, J.J. Nat. Rev. Cancer 15, 7–24 (2015).

    CAS  Article  PubMed Central  Google Scholar 

  6. 6

    Elkabets, M. et al. Sci. Transl. Med. 5, 196ra199 (2013).

    Article  Google Scholar 

  7. 7

    Krueger, D.A. et al. N. Engl. J. Med. 363, 1801–1811 (2010).

    CAS  Article  Google Scholar 

  8. 8

    O'Reilly, T. et al. Cancer Chemother. Pharmacol. 65, 625–639 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Choo, A.Y., Yoon, S.O., Kim, S.G., Roux, P.P. & Blenis, J. Proc. Natl. Acad. Sci. USA 105, 17414–17419 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Creighton, C.J. Oncogene 26, 4648–4655 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Brastianos, P.K. et al. Cancer Discov. 5, 1164–1177 (2015).

    CAS  Article  PubMed Central  Google Scholar 

  12. 12

    Shlien, A. et al. Biallelic Mismatch Repair Deficiency Consortium. Nat. Genet. 47, 257–262 (2015).

    CAS  Article  Google Scholar 

  13. 13

    Hortobagyi, G.N. et al. J. Clin. Oncol. 34, 419–426 (2016).

    CAS  Article  Google Scholar 

  14. 14

    Gentleman, R.C. et al. Genome Biol. 5, R80 (2004).

    Article  PubMed Central  Google Scholar 

  15. 15

    Miller, C.A., Hampton, O., Coarfa, C. & Milosavljevic, A. PLoS One 6, e16327 (2011).

    CAS  Article  PubMed Central  Google Scholar 

  16. 16

    Wang, Y. et al. Cell 163, 174–186 (2015).

    CAS  Article  PubMed Central  Google Scholar 

  17. 17

    Love, M.I., Huber, W. & Anders, S. Genome Biol. 15, 550 (2014).

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank D. Livingston for reading the manuscript. We thank R. Modiste and G. Dai at the Dana-Farber Lurie Family Image Center for MRI imaging. We thank R. Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histoplathology Core for histopathological analyses. We thank F. Pan, D. Light and R. Qi (Life Technologies, Thermo Fisher) for assistance with WES and transcriptome analyses with the Ion Torrent sequencing system. We thank J. Ruan and M. Ruan (VigeneTech) for quantification of pS6RP and p4EBP IHC data by the Cellvigene data-analysis program. This work was supported by the Breast Cancer Research Foundation (N.U.L., E.P.W., Z.W. and J.J.Z.); Aid for Cancer Research (E.P.W. and J.J.Z.); Breast Cancer Alliance (J.J.Z.); Komen scholar grant (E.P.W.); and US National Institutes of Health (NIH) grants R01 CA187918 (T.M.R. and J.J.Z.), CA172461 (J.J.Z.), 1K08NS087118 (S.H.R.), P50 CA165962 (T.M.R., K.L.L. and J.J.Z.), P01 CA142536 (J.J.Z.) and 1P50CA168504 (T.M.R., I.E.K., E.P.W., N.U.L., and J.J.Z.).

Author information

Affiliations

Authors

Contributions

J.N., S.H.R., S.X., E.P.W., N.U.L., K.L.L. and J.J.Z. conceived and designed experiments. J.N., S.H.R., S.X., K.L.L. and J.J.Z. developed methodology. J.N., S.H.R., S.X., H.G., V.L., Y.J.K. and M.H. performed the surgeries and the in vitro and in vivo experiments. J.N., S.H.R., S.X., S.G., D.G.S., E.M., K.L.L. and J.J.Z. analyzed and interpreted data. J.N., S.H.R., S.X., S.G., J.D.I., I.E.K., G.-C.Y., T.M.R., E.P.W., N.U.L., K.L.L. and J.J.Z. wrote and/or revised the manuscript. J.N., S.H.R., S.X., L.A.R., Q.-D.N., A.H.L., R.D., E.B.C., B.M.A. and Z.C.W. provided administrative, technical or material support. H.G., V.L., Y.J.K. and M.H. provided technical assistance. E.P.W., N.U.L., K.L.L. and J.J.Z. supervised and coordinated all aspects of the work.

Corresponding authors

Correspondence to Nancy U Lin or Keith L Ligon or Jean J Zhao.

Ethics declarations

Competing interests

T.M.R. is a consultant of Novartis and has received a research grant from Novartis. E.P.W. has received research grants from Genentech and Roche. I.E.K. is a consultant of Amgen and has received research funding from Genentech. N.U.L. has received research grants from Genentech, Array Biopharma, GlaxoSmithKline, Kadmon and Novartis.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–4 (PDF 4482 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ni, J., Ramkissoon, S., Xie, S. et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22, 723–726 (2016). https://doi.org/10.1038/nm.4120

Download citation

Further reading