Combinatorial Inhibition of PTPN12-regulated Receptors Leads to a Broadly Effective Therapeutic Strategy in Triple-Negative Breast Cancer

Nat Med. 2018 May;24(4):505-511. doi: 10.1038/nm.4507. Epub 2018 Mar 26.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), 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 TNBC. PTPN12 restrains several RTKs, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Crizotinib / pharmacology
  • Crizotinib / therapeutic use
  • Female
  • Humans
  • Mice, Nude
  • Mutation / genetics
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction
  • Sunitinib / pharmacology
  • Sunitinib / therapeutic use
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / enzymology
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Receptors, Cell Surface
  • Crizotinib
  • Receptor Protein-Tyrosine Kinases
  • PTPN12 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12
  • Sunitinib