Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 axis

Nandini Verma, Anna Katharina Müller, Charu Kothari, Effrosini Panayotopoulou, Amir Kedan, Michael Selitrennik, Gordon Mills, Lan K. Nguyen, Sungyoung Shin, Thomas Karn, Uwe Holtrich, Sima Lev

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and is considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the nonreceptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in a mouse xenograft model. Dual targeting of EGFR and PYK2/FAK inhibited complementary key growth and survival pathways mediated by AKT, S6K, STAT3, and ERK1/2 activation. PYK2 inhibition also abrogated HER3 upregulation in response to EGFR antagonists, thereby circumventing HER3-associated drug resistance. Mechanistically, PYK2 inhibition facilitated the proteasomal degradation of HER3 while inducing upregulation of NDRG1 (N-myc downstream regulated 1 gene). NDRG1 enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2, which interacts with NEDD4 and HER3, interfered with NEDD4-HER3 binding, suggesting that the PYK2-NDRG1-NEDD4 circuit has a critical role in receptor degradation, drug response, and resistance mechanism. Our studies offer a preclinical proof of concept for a strategy of cotargeting the EGFR and PYK2/FAK kinases to improve TNBC therapy.

Original languageEnglish (US)
Pages (from-to)86-99
Number of pages14
JournalCancer Research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Triple Negative Breast Neoplasms
Up-Regulation
Drug Resistance
Genes
Gene Regulatory Networks
Ligases
Growth
Ubiquitin
Heterografts
Protein-Tyrosine Kinases
Phosphotransferases
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 axis. / Verma, Nandini; Müller, Anna Katharina; Kothari, Charu; Panayotopoulou, Effrosini; Kedan, Amir; Selitrennik, Michael; Mills, Gordon; Nguyen, Lan K.; Shin, Sungyoung; Karn, Thomas; Holtrich, Uwe; Lev, Sima.

In: Cancer Research, Vol. 77, No. 1, 01.01.2017, p. 86-99.

Research output: Contribution to journalArticle

Verma, N, Müller, AK, Kothari, C, Panayotopoulou, E, Kedan, A, Selitrennik, M, Mills, G, Nguyen, LK, Shin, S, Karn, T, Holtrich, U & Lev, S 2017, 'Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 axis', Cancer Research, vol. 77, no. 1, pp. 86-99. https://doi.org/10.1158/0008-5472.CAN-16-1797
Verma, Nandini ; Müller, Anna Katharina ; Kothari, Charu ; Panayotopoulou, Effrosini ; Kedan, Amir ; Selitrennik, Michael ; Mills, Gordon ; Nguyen, Lan K. ; Shin, Sungyoung ; Karn, Thomas ; Holtrich, Uwe ; Lev, Sima. / Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 axis. In: Cancer Research. 2017 ; Vol. 77, No. 1. pp. 86-99.
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abstract = "Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and is considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the nonreceptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in a mouse xenograft model. Dual targeting of EGFR and PYK2/FAK inhibited complementary key growth and survival pathways mediated by AKT, S6K, STAT3, and ERK1/2 activation. PYK2 inhibition also abrogated HER3 upregulation in response to EGFR antagonists, thereby circumventing HER3-associated drug resistance. Mechanistically, PYK2 inhibition facilitated the proteasomal degradation of HER3 while inducing upregulation of NDRG1 (N-myc downstream regulated 1 gene). NDRG1 enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2, which interacts with NEDD4 and HER3, interfered with NEDD4-HER3 binding, suggesting that the PYK2-NDRG1-NEDD4 circuit has a critical role in receptor degradation, drug response, and resistance mechanism. Our studies offer a preclinical proof of concept for a strategy of cotargeting the EGFR and PYK2/FAK kinases to improve TNBC therapy.",
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AU - Kothari, Charu

AU - Panayotopoulou, Effrosini

AU - Kedan, Amir

AU - Selitrennik, Michael

AU - Mills, Gordon

AU - Nguyen, Lan K.

AU - Shin, Sungyoung

AU - Karn, Thomas

AU - Holtrich, Uwe

AU - Lev, Sima

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