- Title
- Carfilzomib promotes the unfolded protein response and apoptosis in cetuximab-resistant colorectal cancer
- Creator
- Zulkifli, Ahmad; Tan, Fiona; Areeb, Zammam; Stuart, Sarah; Luwor, Rodney
- Date
- 2021
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/178359
- Identifier
- vital:15414
- Identifier
-
https://doi.org/10.3390/ijms22137114
- Identifier
- ISBN:1661-6596 (ISSN)
- Abstract
- Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Rodney Luwor” is provided in this record**
- Publisher
- MDPI AG
- Relation
- International Journal of Molecular Sciences Vol. 22, no. 13 (2021), p.
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Rights
- Open Access
- Subject
- 0399 Other Chemical Sciences; 0604 Genetics; 0699 Other Biological Sciences; Carfilzomib and unfolded protein response; EGFR
- Full Text
- Reviewed
- Funder
- R.B.L. is a recipient of the Victorian Cancer Agency Mid-Career Research Fellowship (MCRF15017).
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