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.
Highlights
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
RAS proteins play a key role in many more cancers through indirect activation, for example, as a result of aberrant signalling by receptor tyrosine kinases (RTKs), or by inactivation of negative regulators such as the NF1 tumour suppressor gene
In this study we show that genetic inhibition of SHOC2 suppresses tumour development and elongates overall survival in KRAS-driven Lung adenocarcinoma (LUAD) mouse models, as well as inhibiting tumorigenic growth in a subset of KRAS- and EGFR-mutant human cell lines
Summary
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. 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. MEK inhibitors (MEKi) are highly selective due to their allosteric mechanism of action but have shown minimal clinical efficacy against RAS-driven tumours[7,8] This is mainly due to drug resistance and toxicity. The ERK-pathway is a key mediator of G1/S transition and MEKi’s have a predominantly cytostatic response that likely facilitates acquisition of drug resistance mechanisms[13] In both RAS- and BRAF-mutant cells, most resistance mechanisms lead to ERK-pathway reactivation, highlighting the strong ‘oncogene addiction’ of these cancers to ERK-signalling. In order to effectively harness the addiction of RAS-mutant cancers to ERK-signalling into viable therapies, new signalling nodes as well as strategies to improve the therapeutic index of current inhibitors are needed[17,18,19,20,21]
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