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

TY - JOUR

T1 - Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer

AU - Nair, Amritha

AU - Chung, Hsiang Ching

AU - Sun, Tingting

AU - Tyagi, Siddhartha

AU - Dobrolecki, Lacey E.

AU - Dominguez-Vidana, Rocio

AU - Kurley, Sarah J.

AU - Orellana, Mayra

AU - Renwick, Alexander

AU - Henke, David M.

AU - Katsonis, Panagiotis

AU - Schmitt, Earlene

AU - Chan, Doug W.

AU - Li, Hui

AU - Mao, Sufeng

AU - Petrovic, Ivana

AU - Creighton, Chad J.

AU - Gutierrez, Carolina

AU - Dubrulle, Julien

AU - Stossi, Fabio

AU - Tyner, Jeffrey

AU - Lichtarge, Olivier

AU - Lin, Charles Y.

AU - Zhang, Bing

AU - Scott, Kenneth L.

AU - Hilsenbeck, Susan G.

AU - Sun, Jinpeng

AU - Yu, Xiao

AU - Osborne, C. Kent

AU - Schiff, Rachel

AU - Christensen, James G.

AU - Shields, David J.

AU - Rimawi, Mothaffar F.

AU - Ellis, Matthew J.

AU - Shaw, Chad A.

AU - Lewis, Michael T.

AU - Westbrook, Thomas F.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85045244070&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045244070&partnerID=8YFLogxK

U2 - 10.1038/nm.4507

DO - 10.1038/nm.4507

M3 - Article

C2 - 29578538

AN - SCOPUS:85045244070

VL - 24

SP - 505

EP - 511

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 4

ER -