SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.
journal contributionposted on 2020-01-09, 11:42 authored by Greg G Jones, Isabel Boned del 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, Pablo Rodriguez-Viciana
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.
AnimalsApoptosisCarcinoma, Non-Small-Cell LungCell Line, TumorDrug Resistance, NeoplasmFemaleHEK293 CellsHumansIntracellular Signaling Peptides and ProteinsLung NeoplasmsMAP Kinase Signaling SystemMaleMice, KnockoutMice, NudeMutationNeoplasm TransplantationProtein Kinase InhibitorsProtein Multimerizationraf Kinasesras ProteinsDownward FC001070