SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers

Greg G. Jones, Isabel Boned Río, Sibel Sari, Aysen Sekerim, Lucy C. Young, Nicole Hartig, Itziar Areso Zubiaur, Mona A. El-Bahrawy, Rob E. Hynds, Winnie Lei, Miriam Molina-Arcas, Julian Downward and Pablo Rodriguez-Viciana ()
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Greg G. Jones: University College London Cancer Institute
Isabel Boned Río: University College London Cancer Institute
Sibel Sari: University College London Cancer Institute
Aysen Sekerim: University College London Cancer Institute
Lucy C. Young: University College London Cancer Institute
Nicole Hartig: University College London Cancer Institute
Itziar Areso Zubiaur: University College London Cancer Institute
Mona A. El-Bahrawy: Imperial College London
Rob E. Hynds: University College London Cancer Institute
Winnie Lei: University College London Cancer Institute
Miriam Molina-Arcas: The Oncogene Biology Lab, The Francis Crick Institute
Julian Downward: The Oncogene Biology Lab, The Francis Crick Institute
Pablo Rodriguez-Viciana: University College London Cancer Institute

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10367-x

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