ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis

Abstract

KRAS is one of the most frequently mutated oncogenes, especially in lung cancers. Targeting of KRAS directly or the downstream effector signaling machinery is of prime interest in treating lung cancers. Here, we uncover that ERK3, a ubiquitously expressed atypical MAPK, is required for KRAS-mediated NSCLC tumors. ERK3 is highly expressed in lung cancers, and oncogenic KRAS led to the activation and stabilization of the ERK3 protein. In particular, phosphorylation of serine 189 in the activation motif of ERK3 is significantly increased in lung adenocarcinomas in comparison to adjacent normal controls in patients. Loss of ERK3 prevents the anchorage-independent growth of KRAS G12C-transformed human bronchial epithelial cells. We further find that loss of ERK3 reduces the oncogenic growth of KRAS G12C-driven NSCLC tumors in vivo and that the kinase activity of ERK3 is required for KRAS-driven oncogenesis in vitro. Our results demonstrate an obligatory role for ERK3 in NSCLC tumor progression and suggest that ERK3 kinase inhibitors can be pursued for treating KRAS G12C-driven tumors.

Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice

“…To our knowledge, our study is the first revealing a bona fide tumor-promoting role for ERK3 in vivo using genetically engineered mouse models. Together with previous findings showing important roles of ERK3 in cultured cells and in xenograft lung tumor model [3,6], our findings corroborate that ERK3 acts as an oncoprotein in promoting LUAD development and progression.…”

“…The kinase activity and cellular functions of ERK3 are positively regulated by phosphorylation of S189 in the activation motif, although it remains elusive regarding the upstream signal for stimulating S189 phosphorylation [5,[39][40][41]. Importantly, the level of S189 phosphorylation, which was determined by mass-spectrometry-based phosphoproteomic analyses in the study, was shown to be significantly elevated in lung adenocarcinomas [6]. These clinic findings suggest that altered ERK3 signaling in cancers is mainly caused by upregulation of expression level and posttranslational modifications rather than genetic mutations.…”

“…More frequent in cancers is the upregulation of ERK3 expression. Several studies, including those in TCGA, have shown the upregulation of ERK3 at both mRNA level and protein level in NSCLC, including both LUAD and LUSC [3,6]. The kinase activity and cellular functions of ERK3 are positively regulated by phosphorylation of S189 in the activation motif, although it remains elusive regarding the upstream signal for stimulating S189 phosphorylation [5,[39][40][41].…”

“…In NSCLCs, the role of ERK3 on cell growth appears to be affected by other molecular alterations in cells. For example, while ERK3 depletion had little effect on the growth of lung cancer cell lines H1299 and H1650 that express wild type KRAS [3,6], it greatly reduced cell growth and/or anchorageindependent colony formation of KRAS G12C -positive H23 and H2122 NSCLC cell lines and xenograft tumor growth of Calu-1 cell line also expressing KRAS G12C [6]. Although KRAS G12Cactivated ERK1/2 signaling is important for the growth of H2122, Calu-1, and H23, ERK3 depletion does not affect MEK/ERK1/2 activity, and its role in promoting cancer cell growth is independent of the ERK1/2 pathway [6].…”

“…Several different molecular mechanisms underlying the cancer-promoting role of ERK3 have been proposed, such as activating SRC-3/PEA3-mediated MMP gene transcription in lung cancers and breast cancer [3] and c-Jun/AP1mediated IL-8 expression in colon cancer cells and MDA-MB231 breast cancer cells [9]. In addition, ERK3 promotes cancer cell growth and invasion in both kinase-dependent [3,6] and kinase-independent mechanisms [5,9]. On the contrary, it is largely unclear how ERK3 inhibits the growth and invasiveness of melanoma and hepatocarcinoma cells.…”