Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion (original) (raw)

References

1. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010)
   Article CAS ADS PubMed PubMed Central Google Scholar
2. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011)
   Article CAS PubMed PubMed Central Google Scholar
3. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010)
   Article CAS PubMed PubMed Central Google Scholar
4. Sosman, J. A. et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012)
   CAS PubMed PubMed Central Google Scholar
5. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009)
   Article CAS Google Scholar
6. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006)
   Article CAS Google Scholar
7. McMillin, D. W. et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nature Med. 16, 483–489 (2010)
   Article CAS PubMed Google Scholar
8. Shekhar, M. P., Santner, S., Carolin, K. A. & Tait, L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am. J. Pathol. 170, 1546–1560 (2007)
   Article CAS PubMed PubMed Central Google Scholar
9. Teicher, B. A. et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247, 1457–1461 (1990)
   Article CAS ADS PubMed Google Scholar
10. Wang, W. et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res. 15, 6630–6638 (2009)
    Article CAS PubMed Google Scholar
11. Williams, R. T., Roussel, M. F. & Sherr, C. J. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of _Bcr–Abl_-induced acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 103, 6688–6693 (2006)
    Article CAS ADS PubMed PubMed Central Google Scholar
12. Puri, N. et al. c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin. Cancer Res. 13, 2246–2253 (2007)
    Article CAS PubMed Google Scholar
13. Lee, Y. J. et al. Expression of the c-Met proteins in malignant skin cancers. Ann. Dermatol. 23, 33–38 (2011)
    Article CAS PubMed PubMed Central Google Scholar
14. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007)
    Article CAS ADS PubMed Google Scholar
15. Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Naturehttp://dx.doi.org/10.1038/nature11249 (2012)
16. Jiang, C. C. et al. MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin. Cancer Res. 17, 721–730 (2011)
    Article CAS PubMed Google Scholar
17. Shao, Y. & Aplin, A. E. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 70, 6670–6681 (2010)
    Article CAS PubMed PubMed Central Google Scholar
18. Villanueva, J. 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)
    Article CAS PubMed PubMed Central Google Scholar
19. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010)
    Article CAS ADS PubMed PubMed Central Google Scholar
20. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010)
    Article CAS ADS PubMed PubMed Central Google Scholar
21. Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011)
    Article CAS ADS PubMed PubMed Central Google Scholar
22. Wang, H. et al. Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the _B-Raf_V600E mutation. Cancer Res. 71, 5535–5545 (2011)
    Article CAS PubMed Google Scholar
23. Corcoran, R. B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012)
    Article CAS PubMed PubMed Central Google Scholar
24. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012)
    Article CAS ADS PubMed Google Scholar
25. Kammula, U. S. et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 248, 219–228 (2007)
    Article CAS PubMed Google Scholar
26. Di Renzo, M. F. et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1, 147–154 (1995)
    CAS PubMed Google Scholar
27. Liu, C., Park, M. & Tsao, M. S. Overexpression of c-met proto-oncogene but not epidermal growth factor receptor or c-erbB-2 in primary human colorectal carcinomas. Oncogene 7, 181–185 (1992)
    CAS PubMed Google Scholar
28. Chan, A. T., Ogino, S. & Fuchs, C. S. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med. 356, 2131–2142 (2007)
    Article CAS PubMed Google Scholar
29. Du, J. et al. Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nature Biotechnol. 27, 77–83 (2009)
    Article CAS Google Scholar
30. Keith, C. T., Borisy, A. A. & Stockwell, B. R. Multicomponent therapeutics for networked systems. Nature Rev. Drug Discov. 4, 71–78 (2005)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank all members of the Golub laboratory for discussions. We thank C. M. Johannessen, I. Rabinowitch, N. Shoresh and A. Goren for critical reading of the manuscript, and L. Gaffney for expert assistance with the graphics. This work was supported by the Howard Hughes Medical Institute, National Cancer Institute grants P50CA093683 and U54CA112962 (T.R.G.) and a Melanoma Research Alliance Team Science Award.

Author information

Authors and Affiliations

1. The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA
   Ravid Straussman, Kevin Shee, Michal Barzily-Rokni, Jinyan Du, Ashli Davis, Margaret M. Mongare, Joshua Gould & Todd R. Golub
2. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA,
   Teppei Morikawa, Zhi Rong Qian & Shuji Ogino
3. Division of Surgical Oncology, Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA,
   Dennie T. Frederick, Zachary A. Cooper, Keith T. Flaherty & Jennifer A. Wargo
4. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA
   Paul B. Chapman & David B. Solit
5. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA
   David B. Solit
6. Division of Hematology and Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 90095, California, USA
   Antoni Ribas
7. Department of Molecular and Medical Pharmacology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 90095, California, USA
   Antoni Ribas & Roger S. Lo
8. Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 90095, California, USA
   Roger S. Lo
9. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA
   Shuji Ogino
10. Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA,
    Todd R. Golub
11. Harvard Medical School, Boston, 02115, Massachusetts, USA
    Todd R. Golub
12. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA
    Todd R. Golub

Authors

1. Ravid Straussman
   You can also search for this author inPubMed Google Scholar
2. Teppei Morikawa
   You can also search for this author inPubMed Google Scholar
3. Kevin Shee
   You can also search for this author inPubMed Google Scholar
4. Michal Barzily-Rokni
   You can also search for this author inPubMed Google Scholar
5. Zhi Rong Qian
   You can also search for this author inPubMed Google Scholar
6. Jinyan Du
   You can also search for this author inPubMed Google Scholar
7. Ashli Davis
   You can also search for this author inPubMed Google Scholar
8. Margaret M. Mongare
   You can also search for this author inPubMed Google Scholar
9. Joshua Gould
   You can also search for this author inPubMed Google Scholar
10. Dennie T. Frederick
    You can also search for this author inPubMed Google Scholar
11. Zachary A. Cooper
    You can also search for this author inPubMed Google Scholar
12. Paul B. Chapman
    You can also search for this author inPubMed Google Scholar
13. David B. Solit
    You can also search for this author inPubMed Google Scholar
14. Antoni Ribas
    You can also search for this author inPubMed Google Scholar
15. Roger S. Lo
    You can also search for this author inPubMed Google Scholar
16. Keith T. Flaherty
    You can also search for this author inPubMed Google Scholar
17. Shuji Ogino
    You can also search for this author inPubMed Google Scholar
18. Jennifer A. Wargo
    You can also search for this author inPubMed Google Scholar
19. Todd R. Golub
    You can also search for this author inPubMed Google Scholar

Contributions

R.S. and T.R.G. conceived and designed the experiments. R.S. performed the primary cancer–stroma–drugs screen with help from K.S., M.B.-R. and A.D. R.S. carried out the protein array experiments. R.S., K.S., M.B.-R., A.D. and M.M.M. carried out the secondary screens, western blot analysis and enzyme-linked immunosorbent assays (ELISAs). J.D. performed tyrosine kinase phosphorylation profiling. Clinical samples and clinical data were collected by J.A.W., K.T.F., D.T.F., P.B.C., D.B.S., A.R. and R.S.L. The immunohistochemistry experiments were carried out and analysed by S.O., T.M. and Z.R.Q. The immunofluorescence experiments were carried out by J.A.W. and Z.A.C. R.S. and T.R.G. produced the text and figures, including the Supplementary Information. K.S. helped to produce some of the text and figures. All authors discussed the results and contributed to the final manuscript.

Corresponding author

Correspondence toTodd R. Golub.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

PowerPoint slides

Rights and permissions

About this article

Cite this article

Straussman, R., Morikawa, T., Shee, K. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.Nature 487, 500–504 (2012). https://doi.org/10.1038/nature11183

Download citation

• Received: 07 November 2011
• Accepted: 04 May 2012
• Published: 04 July 2012
• Issue Date: 26 July 2012
• DOI: https://doi.org/10.1038/nature11183