Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance
The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance o...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Published: |
Elsevier BV
2019
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| Online Access: | http://hdl.handle.net/20.500.11937/74623 |
| _version_ | 1848763326716182528 |
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| author | Hirpara, J. Eu, J. Tan, J. Wong, A. Clement, M. Kong, L. Ohi, N. Tsunoda, T. Qu, J. Goh, B. Pervaiz, Shazib |
| author_facet | Hirpara, J. Eu, J. Tan, J. Wong, A. Clement, M. Kong, L. Ohi, N. Tsunoda, T. Qu, J. Goh, B. Pervaiz, Shazib |
| author_sort | Hirpara, J. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting. |
| first_indexed | 2025-11-14T11:01:41Z |
| format | Journal Article |
| id | curtin-20.500.11937-74623 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T11:01:41Z |
| publishDate | 2019 |
| publisher | Elsevier BV |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-746232019-05-10T02:27:27Z Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance Hirpara, J. Eu, J. Tan, J. Wong, A. Clement, M. Kong, L. Ohi, N. Tsunoda, T. Qu, J. Goh, B. Pervaiz, Shazib The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting. 2019 Journal Article http://hdl.handle.net/20.500.11937/74623 10.1016/j.redox.2018.101076 http://creativecommons.org/licenses/by-nc-nd/4.0/ Elsevier BV fulltext |
| spellingShingle | Hirpara, J. Eu, J. Tan, J. Wong, A. Clement, M. Kong, L. Ohi, N. Tsunoda, T. Qu, J. Goh, B. Pervaiz, Shazib Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance |
| title | Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance |
| title_full | Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance |
| title_fullStr | Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance |
| title_full_unstemmed | Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance |
| title_short | Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance |
| title_sort | metabolic reprogramming of oncogene-addicted cancer cells to oxphos as a mechanism of drug resistance |
| url | http://hdl.handle.net/20.500.11937/74623 |