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Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer

Nature Medicine volume 24, pages 505–511 (2018)Cite this article

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Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year1 and is recalcitrant to targeted therapies2,3. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs)4,5,6,7,8, RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC9,10. PTPN12 restrains several RTKs9,11,12,13,14,15,16,17, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRβ, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRβ and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRβ and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale for combining RTK inhibitors in TNBC and other malignancies that lack receptor-activating mutations.

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Figure 1: The PTPN12 phosphatase inhibits mitogenic RTK signaling in TNBCs.
Figure 2: Tumor-derived PTPN12 mutations impair PTPN12-RTK regulation.
Figure 3: Combinatorial inhibition of PTPN12-regulated RTKs impairs TNBC cell survival.
Figure 4: Crizotinib-Sunitinib combination therapy confers regression in PTPN12-deficient TNBC PDXs.

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Acknowledgements

We would like to thank members of T.F.W. laboratory for helpful comments. The authors also acknowledge the joint participation of the Adrienne Helis Melvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine for cancer research. The Dan L. Duncan Cancer Center Shared Resources was supported by the NCI P30CA125123 Center Grant and provided technical assistance including Cell-Based Assay Screening Service (D. Liu), Biostatistics & Informatics Shared Resource (S. Hilsenbeck), and Cytometry and Cell Sorting (J. Sederstrom; P30 AI036211 and S10 RR024574). M.T.L. was supported by the Susan G. Komen Foundation (KG120001), a NCI/NIH SPORE Supplement Award (P50 CA186784), and the Patient-derived Xenograft and Advance In vivo Models Core at Baylor College of Medicine and P30 Cancer Center Support Grant (NCI-CA125123). T.F.W. was supported by CPRIT (RP120583), the Susan G. Komen Foundation (KG090355), the NIH (1R01CA178039-01) and the DOD Breast Cancer Research Program (BC120604).

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Authors and Affiliations

  1. Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Amritha Nair, Hsiang-Ching Chung, Tingting Sun, Siddhartha Tyagi, Rocio Dominguez-Vidana, Sarah J Kurley, Mayra Orellana, Alexander Renwick, David M Henke, Panagiotis Katsonis, Earlene Schmitt, Olivier Lichtarge, Charles Y Lin, Kenneth L Scott, Chad A Shaw & Thomas F Westbrook

  2. Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Amritha Nair, Hsiang-Ching Chung, Tingting Sun, Siddhartha Tyagi, Rocio Dominguez-Vidana, Sarah J Kurley, Mayra Orellana, Earlene Schmitt & Thomas F Westbrook

  3. Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Hsiang-Ching Chung, Rocio Dominguez-Vidana & Thomas F Westbrook

  4. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Lacey E Dobrolecki, Doug W Chan, Sufeng Mao, Ivana Petrovic, Carolina Gutierrez, Bing Zhang, Susan G Hilsenbeck, C Kent Osborne, Rachel Schiff, Mothaffar F Rimawi, Matthew J Ellis & Michael T Lewis

  5. Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China

    Hui Li & Xiao Yu

  6. Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Chad J Creighton, Kenneth L Scott, Susan G Hilsenbeck, C Kent Osborne, Rachel Schiff, Matthew J Ellis & Thomas F Westbrook

  7. Division of Biostatistics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Chad J Creighton & Susan G Hilsenbeck

  8. Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Carolina Gutierrez

  9. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    Julien Dubrulle, Fabio Stossi, C Kent Osborne, Rachel Schiff, Matthew J Ellis, Michael T Lewis & Thomas F Westbrook

  10. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA

    Jeffrey W Tyner

  11. Therapeutic Innovation Center, Baylor College of Medicine, Houston, Texas, USA

    Charles Y Lin & Thomas F Westbrook

  12. Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Shandong, Jinan, China

    Jinpeng Sun

  13. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA

    C Kent Osborne, Rachel Schiff & Matthew J Ellis

  14. Oncology Research Unit, Pfizer Global Research and Development, La Jolla, San Diego, California, USA

    James G Christensen & David J Shields

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Contributions

A.N., H.-C.C., T.S., S.T., L.E.D., R.D.-V., S.J.K., M.O., D.W.C., S.M., I.P. and E.S. performed the experiments. A.R., R.D.-V. and D.M.H. performed statistical analyses. R.D.-V. and P.K. performed the analysis shown in Figure 2a. P.K. performed the analysis shown in Figure 2b,c. H.L. performed the experiments shown in Figure 2d and Supplementary Figure 6a. C.J.C. performed the TCGA analysis shown in Figure 1e. J.D. and F.S. performed the image analysis shown in Figure 1h,i. A.N., C.G., J.W.T., O.L., C.Y.L., B.Z., K.L.S., S.G.H., J.S., X.Y., C.K.O., R.S., J.G.C., D.J.S., M.F.R., M.J.E., C.A.S., M.T.L. and T.F.W. devised or supervised experiments. A.N. and T.F.W. wrote the manuscript.

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Correspondence to Thomas F Westbrook.

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Competing interests

D.J.S. is an employee of Pfizer. J.G.C. is an employee of Mirati Therapeutics and former employee of Pfizer.

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Nair, A., Chung, HC., Sun, T. et al. Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer. Nat Med 24, 505–511 (2018). https://doi.org/10.1038/nm.4507

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