Oncotarget

Research Papers:

A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib

Nancy D. Ebelt, Tamer S. Kaoud, Ramakrishna Edupuganti, Sabrina Van Ravenstein, Kevin N. Dalby and Carla L. Van _

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Oncotarget. 2017; 8:104894-104912. https://doi.org/10.18632/oncotarget.20581

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Abstract

Nancy D. Ebelt1,2, Tamer S. Kaoud2,4, Ramakrishna Edupuganti2, Sabrina Van Ravenstein2, Kevin N. Dalby2 and Carla L. Van Den Berg1,3

1Institute of Cellular & Molecular Biology, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA

2Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA

3Division of Pharmacology & Toxicology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA

4Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, El-Minia 61519, Egypt

Correspondence to:

Carla L. Van Den Berg, email: carla.vandenberg@austin.utexas.edu

Keywords: triple negative breast cancer, lapatinib, JNK, oxidative stress, antioxidant

Received: July 05, 2017    Accepted: August 04, 2017    Published: August 24, 2017

ABSTRACT

Triple negative breast cancers (TNBC) have poor prognosis compared to other breast cancer subtypes and represent 15-20% of breast cancers diagnosed. Unique targets and new molecularly-targeted therapies are urgently needed for this subtype. Despite high expression of Epidermal Growth Factor Receptor, inhibitors such as lapatinib have not shown therapeutic efficacy in TNBC patients. Herein, we report that treatment with the covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death, while these compounds as single agents have little effect. The combination significantly increases survival of mice bearing xenografts of MDA-MB-231 human TNBC cells. Our studies demonstrate that lapatinib treatment increases c-Jun and JNK phosphorylation indicating a mechanism of resistance. Combined, these compounds significantly reduce transcriptional activity of Nuclear Factor kappa B, Activating Protein 1, and Nuclear factor erythroid 2-Related Factor 2. As master regulators of antioxidant response, their decreased activity induces a 10-fold increase in reactive oxygen species that is cytotoxic, and is rescued by addition of exogenous antioxidants. Over expression of p65 or Nrf2 also significantly rescues viability during JNK-IN-8 and lapatinib treatment. Further studies combining JNK-IN-8 and lapatinib may reveal a benefit for patients with TNBC, fulfilling a critical medical need.


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