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

Amritha Nair, Hsiang Ching Chung, Tingting Sun, Siddhartha Tyagi, Lacey E. Dobrolecki, Rocio Dominguez-Vidana, Sarah J. Kurley, Mayra Orellana, Alexander Renwick, David M. Henke, Panagiotis Katsonis, Earlene Schmitt, Doug W. Chan, Hui Li, Sufeng Mao, Ivana Petrovic, Chad J. Creighton, Carolina Gutierrez, Julien Dubrulle, Fabio StossiJeffrey Tyner, Olivier Lichtarge, Charles Y. Lin, Bing Zhang, Kenneth L. Scott, Susan G. Hilsenbeck, Jinpeng Sun, Xiao Yu, C. Kent Osborne, Rachel Schiff, James G. Christensen, David J. Shields, Mothaffar F. Rimawi, Matthew J. Ellis, Chad A. Shaw, Michael T. Lewis, Thomas F. Westbrook

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)505-511
Number of pages7
JournalNature Medicine
Volume24
Issue number4
DOIs
StatePublished - May 1 2018

Fingerprint

Triple Negative Breast Neoplasms
Receptor Protein-Tyrosine Kinases
Tumors
Therapeutics
Neoplasms
Feedback
Proto-Oncogene Proteins c-met
Mutation
Ports and harbors
Phosphoric Monoester Hydrolases
Refractory materials
Protein-Tyrosine Kinases
Tyrosine
Proteins
Chemical activation
Cells
Apoptosis
Breast Neoplasms
Ligands

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nair, A., Chung, H. C., Sun, T., Tyagi, S., Dobrolecki, L. E., Dominguez-Vidana, R., ... Westbrook, T. F. (2018). Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer. Nature Medicine, 24(4), 505-511. https://doi.org/10.1038/nm.4507

Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer. / Nair, Amritha; Chung, Hsiang Ching; Sun, Tingting; Tyagi, Siddhartha; Dobrolecki, Lacey E.; Dominguez-Vidana, Rocio; Kurley, Sarah J.; Orellana, Mayra; Renwick, Alexander; Henke, David M.; Katsonis, Panagiotis; Schmitt, Earlene; Chan, Doug W.; Li, Hui; Mao, Sufeng; Petrovic, Ivana; Creighton, Chad J.; Gutierrez, Carolina; Dubrulle, Julien; Stossi, Fabio; Tyner, Jeffrey; Lichtarge, Olivier; Lin, Charles Y.; Zhang, Bing; Scott, Kenneth L.; Hilsenbeck, Susan G.; Sun, Jinpeng; Yu, Xiao; Osborne, C. Kent; Schiff, Rachel; Christensen, James G.; Shields, David J.; Rimawi, Mothaffar F.; Ellis, Matthew J.; Shaw, Chad A.; Lewis, Michael T.; Westbrook, Thomas F.

In: Nature Medicine, Vol. 24, No. 4, 01.05.2018, p. 505-511.

Research output: Contribution to journalArticle

Nair, A, Chung, HC, Sun, T, Tyagi, S, Dobrolecki, LE, Dominguez-Vidana, R, Kurley, SJ, Orellana, M, Renwick, A, Henke, DM, Katsonis, P, Schmitt, E, Chan, DW, Li, H, Mao, S, Petrovic, I, Creighton, CJ, Gutierrez, C, Dubrulle, J, Stossi, F, Tyner, J, Lichtarge, O, Lin, CY, Zhang, B, Scott, KL, Hilsenbeck, SG, Sun, J, Yu, X, Osborne, CK, Schiff, R, Christensen, JG, Shields, DJ, Rimawi, MF, Ellis, MJ, Shaw, CA, Lewis, MT & Westbrook, TF 2018, 'Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer', Nature Medicine, vol. 24, no. 4, pp. 505-511. https://doi.org/10.1038/nm.4507
Nair, Amritha ; Chung, Hsiang Ching ; Sun, Tingting ; Tyagi, Siddhartha ; Dobrolecki, Lacey E. ; Dominguez-Vidana, Rocio ; Kurley, Sarah J. ; Orellana, Mayra ; Renwick, Alexander ; Henke, David M. ; Katsonis, Panagiotis ; Schmitt, Earlene ; Chan, Doug W. ; Li, Hui ; Mao, Sufeng ; Petrovic, Ivana ; Creighton, Chad J. ; Gutierrez, Carolina ; Dubrulle, Julien ; Stossi, Fabio ; Tyner, Jeffrey ; Lichtarge, Olivier ; Lin, Charles Y. ; Zhang, Bing ; Scott, Kenneth L. ; Hilsenbeck, Susan G. ; Sun, Jinpeng ; Yu, Xiao ; Osborne, C. Kent ; Schiff, Rachel ; Christensen, James G. ; Shields, David J. ; Rimawi, Mothaffar F. ; Ellis, Matthew J. ; Shaw, Chad A. ; Lewis, Michael T. ; Westbrook, Thomas F. / Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer. In: Nature Medicine. 2018 ; Vol. 24, No. 4. pp. 505-511.
@article{f9c635274033479ca6c3f854a120b9a9,
title = "Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer",
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.",
author = "Amritha Nair and Chung, {Hsiang Ching} and Tingting Sun and Siddhartha Tyagi and Dobrolecki, {Lacey E.} and Rocio Dominguez-Vidana and Kurley, {Sarah J.} and Mayra Orellana and Alexander Renwick and Henke, {David M.} and Panagiotis Katsonis and Earlene Schmitt and Chan, {Doug W.} and Hui Li and Sufeng Mao and Ivana Petrovic and Creighton, {Chad J.} and Carolina Gutierrez and Julien Dubrulle and Fabio Stossi and Jeffrey Tyner and Olivier Lichtarge and Lin, {Charles Y.} and Bing Zhang and Scott, {Kenneth L.} and Hilsenbeck, {Susan G.} and Jinpeng Sun and Xiao Yu and Osborne, {C. Kent} and Rachel Schiff and Christensen, {James G.} and Shields, {David J.} and Rimawi, {Mothaffar F.} and Ellis, {Matthew J.} and Shaw, {Chad A.} and Lewis, {Michael T.} and Westbrook, {Thomas F.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1038/nm.4507",
language = "English (US)",
volume = "24",
pages = "505--511",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",

}

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 -