SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.
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Date
2019-06-10ICR Author
Author
Jones, GG
Del Río, IB
Sari, S
Sekerim, A
Young, LC
Hartig, N
Areso Zubiaur, I
El-Bahrawy, MA
Hynds, RE
Lei, W
Molina-Arcas, M
Downward, J
Rodriguez-Viciana, P
Type
Journal Article
Metadata
Show full item recordAbstract
Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.
Collections
Subject
Cell Line, Tumor
Animals
Mice, Knockout
Humans
Mice, Nude
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
ras Proteins
raf Kinases
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Neoplasm Transplantation
Apoptosis
MAP Kinase Signaling System
Drug Resistance, Neoplasm
Mutation
Female
Male
Protein Multimerization
HEK293 Cells
Research team
Lung Cancer Group
Language
eng
Date accepted
2019-05-08
License start date
2019-06-10
Citation
Nature communications, 2019, 10 (1), pp. 2532 - ?