Abstract
Tumours manage to survive the ablation of mutant KRAS, despite the development of KRAS-targeted drugs. Here we describe that inhibition of mutant KRAS promotes MEK nuclear localization as an alternative mechanism of KRAS-targeted drugs resistance. Tissue microarray analysis in colon tumours shows that aberrant MEK nuclear localization is closely related to YAP levels and tumour malignancy. MEK nuclear localization could sequester β-TrCP from cytoplasmic inactive YAP, then stabilizing YAP. Mutant KRAS restrains MEK within the cytoplasm via IQGAP1, inhibiting MEK nuclear translocation. Trametinib, an allosteric MEK inhibitor, could prevent MEK nuclear localization and subsequently promote YAP degradation. In vitro and in vivo results suggests that inhibition of MEK nuclear localization by trametinib synergizes with KRAS knockdown or deltarasin treatment in suppressing the viability of KRAS mutant colon cancer cells. Our study provides new insights into the mechanisms of resistance to KRAS ablation, and suggests novel strategies for the treatment of KRAS-mutant colon cancers.
Highlights
Somatic mutations in KRAS are the most common activating lesions in human cancers, including pancreas, lung and colon cancers [1]
Using co-immunoprecipitation, we found an unexpected interaction between Mitogen-activated protein kinase kinase (MEK) and β-TrCP in SW1116 cells (Fig. 1a)
The nuclear translocation of MEK triggered by mutant KRAS/IQ motif containing GTPase-activating protein 1 (IQGAP1) inhibition indicated that the MEK/ERK kinase activities were dispensable
Summary
Somatic mutations in KRAS are the most common activating lesions in human cancers, including pancreas, lung and colon cancers [1]. The multiple signalling pathways engaged by mutant KRAS form the foundation for its diverse biological roles in proliferation, survival, metabolism and tumour microenvironment remodelling [2]. Some promising inhibitors, such as ARS-853 [3], deltarasin [4], rigosertib [5], exosomes [6] and AZD4785 [7] have renewed hope for the development of. These authors contributed : Huanji Xu, Sheng Zhou, Hongwei Xia. Edited by R.
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