TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response
| العنوان: | TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response |
|---|---|
| المؤلفون: | Penny E. Lovat, Yi-Hsuan Ho, Chiao-En Wu, John Lunec, Tsin Shue Koay |
| المصدر: | Cancer Cell International Cancer Cell International, Vol 19, Iss 1, Pp 1-15 (2019) |
| بيانات النشر: | BioMed Central, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | MAPK/ERK pathway, p53, Cancer Research, Caspase 3, lcsh:RC254-282, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MDM2, Trametinib, Genetics, medicine, lcsh:QH573-671, Vemurafenib, RG7388, Melanoma, HDM201, lcsh:Cytology, Chemistry, Nutlin-3, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Oncology, Cell culture, Apoptosis, 030220 oncology & carcinogenesis, Cancer research, Growth inhibition, Primary Research, medicine.drug |
| الوصف: | Background Emergence of resistance to molecular targeted therapy constitutes a limitation to clinical benefits in cancer treatment. Cross-resistance commonly happens with chemotherapeutic agents but might not with targeted agents. Methods In the current study, TP53 wild-type cell lines with druggable MAPK pathway mutations [BRAFV600E (WM35) or NRAS Q61K (SJSA-1)] were compared with their TP53 mutant sublines (WM35-R, SN40R2) derived by selection for resistance to MDM2/p53 binding antagonists. Results The continued presence of the druggable MAPK pathway targets in the TP53 mutant (TP53MUT) WM35-R and SN40R2 cells was confirmed. Trametinib and vemurafenib were tested on the paired WM35/WM35-R and SJSA-1/SN40R2 cells and similar growth inhibitory effects on the paired cell lines was observed. However, apoptotic responses to trametinib and vemurafenib were greater in WM35 than WM35-R, evidenced by FACS analysis and caspase 3/7 activity, indicating that these MAPK inhibitors acted on the cells partially through p53-regulated pathways. SiRNA mediated p53 knockdown in WM35 replicated the same pattern of response to trametinib and vemurafenib as seen in WM35-R, confirming that p53 plays a role in trametinib and vemurafenib induced apoptosis. In contrast, these differences in apoptotic response between WM35 and WM35-R were not seen with the SJSA-1/SN40R2 cell line pair. This is likely due to p53 suppression by overexpressed MDM2 in SJSA-1. Conclusion The TP53MUT cells selected by resistance to MDM2 inhibitors nevertheless retained growth inhibitory but not apoptotic response to MAPK pathway inhibitors. Electronic supplementary material The online version of this article (10.1186/s12935-019-0768-3) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1475-2867 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7781441058bca3a9cfc372a797f2c20c http://europepmc.org/articles/PMC6407233 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7781441058bca3a9cfc372a797f2c20c |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14752867 |
|---|