| Autor: |
Bao B; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Mitrea C; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Wijesinghe P; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Marchetti L; The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Rovereto, Italy., Girsch E; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Farr RL; Department of Pharmacology, Wayne State University School of Medicine, Detroit MI 48201, USA., Boerner JL; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Mohammad R; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.; Translational Research Institute, Hamad Medical Corporation, Doha, Qatar., Dyson G; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Terlecky SR; Department of Pharmacology, Wayne State University School of Medicine, Detroit MI 48201, USA., Bollig-Fischer A; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA. |
| Abstrakt: |
Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c. |
