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Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways

Nature Medicine volume 17, pages 461–469 (2011)Cite this article

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Abstract

Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.

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Figure 1: SRC hyperactivation is a key signaling alteration in acquired trastuzumab-resistant cells.
Figure 2: SRC is activated in PTEN-deficient de novo trastuzumab-resistant cells.
Figure 3: SRC is a key modulator of trastuzumab response.
Figure 4: SRC inhibition induced signaling alterations in multiple trastuzumab-resistant models.
Figure 5: Trastuzumab treatment plus SRC inhibition overcomes multiple resistance mechanisms in vitro.
Figure 6: Trastuzumab plus saracatinib combinatorial treatment overcomes trastuzumab resistance in vivo.

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Acknowledgements

We thank AstraZeneca for providing us with saracatinib and W. Zhang in the Department of Pathology, MD Anderson Cancer Center for providing us with the IGF-1R expression vector. We also thank C. Neal, J. Lu, S. Rehman and F.J. Lowery for insightful comments on this manuscript. This work was supported by US National Institutes of Health grants P30-CA 16672 (MD Anderson Cancer Center), RO1-CA112567 (D.Y.), PO1-CA099031 project 4 (D.Y.), MD Anderson Cancer Center Breast SPORE P50 CA116199 (G.N.H.) project 4 (D.Y.), US Department of Defense Center of Excellence subproject W81XWH-06-2-0033 (D.Y.), Susan G. Komen Breast Cancer Foundation promise grant KG091020 (D.Y.), Cancer Prevention Research Institute of Texas grant RP100726 (D.Y.), the MD Anderson Cancer Center Breast SPORE Career Development Award (S.Z.) and the Susan G. Komen Breast Cancer Foundation postdoctoral fellowship (S.Z.). D.Y. is the Hubert L. and Olive Stringer Distinguished Chair in Basic Science at MD Anderson Cancer Center.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Siyuan Zhang, Wen-Chien Huang, Ping Li, Hua Guo, Say-Bee Poh, Samuel W Brady, Yan Xiong, Ling-Ming Tseng, Shau-Hsuan Li, Zhaoxi Ding, Francisco J Esteva & Dihua Yu

  2. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

    Samuel W Brady, Francisco J Esteva & Dihua Yu

  3. Department of Pathology, MD Anderson Cancer Center, Houston, Texas, USA

    Aysegul A Sahin

  4. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA

    Francisco J Esteva & Gabriel N Hortobagyi

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Contributions

S.Z., W.-C.H. and D.Y. designed experiments and analyzed data; S.Z., W.-C.H., H.G., P.L., S.-B.P., S.W.B., Y.X., L.-M.T. and Z.D. carried out experiments; S.Z., H.G. and S.-H.L. did statistical analysis of clinical data; A.A.S. collected tumor samples and evaluated immunohistochemistry staining with H.G.; G.N.H. and F.J.E. collected clinical patient information and analyzed patient response data; S.Z., S.W.B. and D.Y. wrote the manuscript.

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Correspondence to Dihua Yu.

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Zhang, S., Huang, WC., Li, P. et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 17, 461–469 (2011). https://doi.org/10.1038/nm.2309

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