title: Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4-NDRG1 Axis.
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. Cancer Res; 77(1); 86-99. ©2016 AACR.
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Nandini
authors: N
authors: Verma
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Anna-Katharina
authors: AK
authors: Müller
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Charu
authors: C
authors: Kothari
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Effrosini
authors: E
authors: Panayotopoulou
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Amir
authors: A
authors: Kedan
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Michael
authors: M
authors: Selitrennik
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Gordon B
authors: GB
authors: Mills
authors: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
authors: Lan K
authors: LK
authors: Nguyen
authors: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
authors: Sungyoung
authors: S
authors: Shin
authors: Department of Obstetrics and Gynecology, Goethe University Frankfurt, Frankfurt, Germany.
authors: Thomas
authors: T
authors: Karn
authors: Department of Obstetrics and Gynecology, Goethe University Frankfurt, Frankfurt, Germany.
authors: Uwe
authors: U
authors: Holtrich
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. sima.lev@weizmann.ac.il.
authors: Sima
authors: S
authors: Lev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D004357:Drug Synergism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005455:Fluorescent Antibody Technique; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D066246:ErbB Receptors; D051418:Focal Adhesion Kinase 2; D000077156:Gefitinib; D047908:Intracellular Signaling Peptides and Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020893:Receptor, ErbB-3; D044767:Ubiquitin-Protein Ligases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; C512478:EGFR protein, human; C581292:ERBB3 protein, human