Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity
| Autor: | Rebecca L. Farr, Cristina Mitrea, Greg Dyson, Aliccia Bollig-Fischer, Priyanga Wijesinghe, Stanley R. Terlecky, Emily Girsch, Bin Bao, Ramzi M. Mohammad, Julie L. Boerner, Luca Marchetti |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology CA15-3 medicine.medical_specialty Triple Negative Breast Neoplasms Article Antioxidants Breast cancer triple negative breast cancer computational biology Erlotinib Hydrochloride 03 medical and health sciences 0302 clinical medicine Breast cancer triple negative breast cancer computational biology Internal medicine medicine Humans Triple-negative breast cancer EGFR inhibitors Multidisciplinary Oncogene business.industry Cancer medicine.disease 3. Good health 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Female Erlotinib business medicine.drug |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep44125 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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