Jones, Greg G del Río, Isabel Boned Sari, Sibel Sekerim, Aysen Young, Lucy C Hartig, Nicole Zubiaur, Itziar Areso El-Bahrawy, Mona A Hynds, Rob E Lei, Winnie Arcas, Miriam Molina Downward, Julian Rodriguez-Viciana, Pablo SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers. 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. Animals;Apoptosis;Carcinoma, Non-Small-Cell Lung;Cell Line, Tumor;Drug Resistance, Neoplasm;Female;HEK293 Cells;Humans;Intracellular Signaling Peptides and Proteins;Lung Neoplasms;MAP Kinase Signaling System;Male;Mice, Knockout;Mice, Nude;Mutation;Neoplasm Transplantation;Protein Kinase Inhibitors;Protein Multimerization;raf Kinases;ras Proteins;Downward FC001070 2020-01-09
    https://crick.figshare.com/articles/journal_contribution/SHOC2_phosphatase-dependent_RAF_dimerization_mediates_resistance_to_MEK_inhibition_in_RAS-mutant_cancers_/11558166