دورية أكاديمية
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TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response.

التفاصيل البيبلوغرافية
العنوان: TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response.
المؤلفون: Wu CE; 1Northern Institute for Cancer Research, School of Medicine, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH UK.; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan., Koay TS; 1Northern Institute for Cancer Research, School of Medicine, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH UK., Ho YH; 1Northern Institute for Cancer Research, School of Medicine, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH UK., Lovat P; 3Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle, UK., Lunec J; 1Northern Institute for Cancer Research, School of Medicine, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH UK.
المصدر: Cancer cell international [Cancer Cell Int] 2019 Mar 07; Vol. 19, pp. 53. Date of Electronic Publication: 2019 Mar 07 (Print Publication: 2019).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101139795 Publication Model: eCollection Cited Medium: Print ISSN: 1475-2867 (Print) Linking ISSN: 14752867 NLM ISO Abbreviation: Cancer Cell Int Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central, [2001-
مستخلص: 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 [ BRAF V600E (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 ( TP53 MUT ) 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 TP53 MUT cells selected by resistance to MDM2 inhibitors nevertheless retained growth inhibitory but not apoptotic response to MAPK pathway inhibitors.
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فهرسة مساهمة: Keywords: HDM201; MDM2; Melanoma; Nutlin-3; RG7388; Trametinib; Vemurafenib; p53
تواريخ الأحداث: Date Created: 20190323 Latest Revision: 20220408
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6407233
DOI: 10.1186/s12935-019-0768-3
PMID: 30899200
قاعدة البيانات: MEDLINE
الوصف
تدمد:1475-2867
DOI:10.1186/s12935-019-0768-3