Letter | Published:

Therapy-induced tumour secretomes promote resistance and tumour progression

Nature volume 520, pages 368372 (16 April 2015) | Download Citation

Abstract

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer1,2. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

All RNA-seq data has been deposited in the Gene Expression Omnibus database under accession number GSE64741.

References

  1. 1.

    & Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr. Opin. Genet. Dev. 18, 73–79 (2008)

  2. 2.

    , , & Cancer drug resistance: an evolving paradigm. Nature Rev. Cancer 13, 714–726 (2013)

  3. 3.

    et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011)

  4. 4.

    et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012)

  5. 5.

    & ALK in lung cancer: past, present, and future. J. Clin. Oncol. 31, 1105–1111 (2013)

  6. 6.

    et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12, 735–742 (2011)

  7. 7.

    et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683–695 (2010)

  8. 8.

    et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010)

  9. 9.

    et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011)

  10. 10.

    et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29, 3085–3096 (2011)

  11. 11.

    et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22, 668–682 (2012)

  12. 12.

    et al. Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nature Commun. 3, 724–728 (2012)

  13. 13.

    et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012)

  14. 14.

    et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012)

  15. 15.

    et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504, 138–142 (2013)

  16. 16.

    et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discovery 4, 69–79 (2014)

  17. 17.

    et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012)

  18. 18.

    et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discovery 4, 80–93 (2014)

  19. 19.

    et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010)

  20. 20.

    et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009)

  21. 21.

    & Melanoma and the tumor microenvironment. Curr. Oncol. Rep. 10, 439–446 (2008)

  22. 22.

    et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012)

  23. 23.

    et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Med. 18, 1359–1368 (2012)

  24. 24.

    et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26, 207–221 (2014)

  25. 25.

    , & Tumor adaptation and resistance to RAF inhibitors. Nature Med. 19, 1401–1409 (2013)

  26. 26.

    et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508, 118–122 (2014)

  27. 27.

    et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc. Natl Acad. Sci. USA 107, 14903–14908 (2010)

  28. 28.

    et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008)

  29. 29.

    & Programmed cell death in animal development and disease. Cell 147, 742–758 (2011)

  30. 30.

    et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517, 209–213 (2015)

  31. 31.

    et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008)

  32. 32.

    et al. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135, 749–762 (2008)

  33. 33.

    et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154, 1060–1073 (2013)

  34. 34.

    et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013)

  35. 35.

    & Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010)

  36. 36.

    , & Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

  37. 37.

    , , & REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS ONE 6, e21800 (2011)

  38. 38.

    et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014)

Download references

Acknowledgements

We thank members of the Massagué laboratory for discussions; L. Sevenich and L. Akkari for technical advice. This work was supported by grants from the AACR (SU2C) to R.S.L., the MSK Metastasis Research Center, the NIH (CA163167 and CA129243), the Congressionally Directed Medical Research Program of the Department of Defense, the Howard Hughes Medical Institute, and the Cancer Center Support Grant P30 CA008748 to J.M., A.C.O. was an Erwin Schroedinger Fellowship awardee (J3013, FWF, Austrian Science Fund). A.L.J. was a Medical Research Fellow of the Howard Hughes Medical Institute. S.V. is supported by the Medical Research Council.

Author information

Author notes

    • Yilong Zou
    •  & Andrew L. Ji

    These authors contributed equally to this work.

Affiliations

  1. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Anna C. Obenauf
    • , Yilong Zou
    • , Andrew L. Ji
    • , Sakari Vanharanta
    • , Weiping Shu
    •  & Joan Massagué
  2. Gerstner Sloan Kettering School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Yilong Zou
  3. MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK

    • Sakari Vanharanta
  4. Division of Dermatology, Department of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA

    • Hubing Shi
    • , Xiangju Kong
    •  & Roger S. Lo
  5. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Marcus C. Bosenberg
  6. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Marcus C. Bosenberg
  7. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Thomas Wiesner
  8. Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Neal Rosen

Authors

  1. Search for Anna C. Obenauf in:

  2. Search for Yilong Zou in:

  3. Search for Andrew L. Ji in:

  4. Search for Sakari Vanharanta in:

  5. Search for Weiping Shu in:

  6. Search for Hubing Shi in:

  7. Search for Xiangju Kong in:

  8. Search for Marcus C. Bosenberg in:

  9. Search for Thomas Wiesner in:

  10. Search for Neal Rosen in:

  11. Search for Roger S. Lo in:

  12. Search for Joan Massagué in:

Contributions

A.C.O. and J.M. conceived the project, designed the experiments and wrote the paper. A.C.O. performed experiments and computational analysis. A.L.J., Y.Z., W.S. and T.W. assisted with experiments. Y.Z. and S.V. performed computational analysis. M.C.B. provided cell lines. X.K., H.S. and R.S.L. provided patient samples. N.R. provided clinical expertise, cell lines and drugs. All authors interpreted data, discussed results, and revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joan Massagué.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Information

    This file contains Supplementary Table 1.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature14336

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.