SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.
Loading...
Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-06-10
Date Accepted
2019-05-08
Abstract
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.
Citation
Nature communications, 2019, 10 (1), pp. 2532 - ?
Source Title
Publisher
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Lung Cancer Group