PTPN12 deficiency may confer sensitivity to tyrosine kinase inhibitor combinations in TNBC.

  • Major finding: PTPN12 deficiency may confer sensitivity to tyrosine kinase inhibitor combinations in TNBC.

  • Mechanism: The tyrosine phosphatase PTPN12 inactivates multiple target RTKs, including MET, PDGFRβ, EGFR, and HER2.

  • Impact: Treatment with multiple receptor tyrosine kinase inhibitors may be effective in patients with TNBC.

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Inhibitors of receptor tyrosine kinases (RTK) largely lack clinical activity in patients with triple-negative breast cancer (TNBC) despite hyperactivation of multiple RTKs. One mechanism by which RTKs may be hyperactivated in TNBC is by loss of the tumor suppressor PTPN12, a tyrosine phosphatase suggested to restrain RTK signaling. However, it is not known which RTKs are targeted by PTPN12, prompting Nair and colleagues to identify PTPN12 substrates with the aim of identifying combination RTK-inhibitor therapies that might be effective in TNBC. PTPN12 reduced tyrosine phosphorylation of four RTKs, MET, PDGFRβ, EGFR, HER2, that were broadly expressed in primary TNBCs and patient-derived xenografts (PDX), suggesting that these RTKs may promote TNBC tumorigenesis. Recurrent mutations affecting the H230 residue of PTPN12 were observed in patients with TNBC and other tumor types, and the H230Y mutation impaired phosphatase activity, resulting in increased phosphorylation of MET and PDGFRβ and reliving the suppression of TNBC cell growth. These findings suggest the potential for therapeutic targeting of PTPN12-regulated RTKs in TNBC. Indeed, PTPN12-deficient TNBC models were sensitive to combined treatment with the tyrosine kinase inhibitors (TKI) crizotinib and sunitinib, but not to either as a single agent. Crizotinib plus sunitinib induced apoptosis in vitro, and induced regression of TNBC xenografts in vivo. Mechanistically, this combination reduced phosphorylation of MET and PDGFRβ. Crizotinib plus sunitinib produced tumor regressions in 7 of 14 PDXs derived from patients with TNBC, and efficacy was linked to reduced PTPN12 levels. Further, combined treatment produced no obvious toxicities. In addition to identifying the RTKs activated by PTPN12 loss in TNBC, these findings suggest that PTPN12-deficient TNBCs may be sensitive to TKI combination therapies.

Nair A, Chung HC, Sun T, Tyagi S, Dobrolecki LE, Dominguez-Vidana R, et al. Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer. Nat Med 2018 Mar 26 [Epub ahead of print].

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