Insights into significance of combined inhibition of MEK and m-TOR signalling output in KRAS mutant non-small-cell lung cancer.
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Authors
Broutin, S
Stewart, A
Thavasu, P
Paci, A
Bidart, J-M
Banerji, U
Stewart, A
Thavasu, P
Paci, A
Bidart, J-M
Banerji, U
Document Type
Journal Article
Date
2016-08-23
Date Accepted
2016-06-23
Abstract
BACKGROUND: We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines. METHODS: In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. RESULTS: GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10(-4)). There was no significant difference in GI caused by maximal m-TOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRAS(M) cell lines (79% vs 61%, P=0.017). CONCLUSIONS: m-TOR inhibition was more critical to GI than MEK inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRAS(M) cells.
Citation
British journal of cancer, 2016, 115 (5), pp. 549 - 552
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0007-0920
eISSN
1532-1827
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Research Team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Medicine Drug Development Unit (de Bono)