MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance

Abstract

The RAS/RAF/MEK/MAPK kinase pathway has been extensively studied for more than 25 years, yet we continue to be puzzled by its intricate dynamic control and plasticity. Different spatiotemporal MAPK dynamics bring about distinct cell fate decisions in normal vs cancer cells and developing organisms. Recent modelling and experimental studies provided novel insights in the versatile MAPK dynamics concerted by a plethora of feedforward/feedback regulations and crosstalk on multiple timescales. Multiple cancer types and various developmental disorders arise from persistent alterations of the MAPK dynamics caused by RAS/RAF/MEK mutations. While a key role of the MAPK pathway in multiple diseases made the development of novel RAF/MEK inhibitors a hot topic of drug development, these drugs have unexpected side-effects and resistance inevitably occurs. We review how RAF dimerization conveys drug resistance and recent breakthroughs to overcome this resistance.

BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

“…Next, we wanted to know which signaling pathway was involved in this process. The MAPK signaling pathway has been widely reported to link with carcinogenesis, with MEK and ERK being two critical kinases in this pathway (Rauch et al, 2016, Zhu et al, 2007). Therefore, p-MEK1/2 (ser221) and p-ERK1/2 (T202/Y204) levels were tested in JB6 Cl41 and WiDr BCKDK stable cell lines, and the results indicated that the level of p-MEK and p-ERK were up-regulated when BCKDK was overexpressed (Fig.…”

Oligodendrocyte RasG12V expressed in its endogenous locus disrupts myelin structure through increased MAPK, nitric oxide, and notch signaling

“…Differences in myelin phenotypes may be due to the mutants analyzed and their effects on levels of RAS activation. Mechanistically, Ras‐GTP activation of ERK1/ERK2 activates feedback regulation that dampens or enhances Ras signaling (Rauch, Rukhlenko, Kolch, & Kholodenko, ). For example, the Ras‐MAPK negative regulator Sprouty 2, induced on growth factor stimulation through MAPK, is highly expressed in the brain, where it dampens the impact of MAPK pathway activation in germline‐ HRasG12V mutants.…”

Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies

“…Additionally, metformin reversed resistance to crizotinib [50]. These effects were accompanied by decreased IGF1-R signaling and a reduction in the IGF-1 induced phosphorylation of mTOR and p70S6K [19]. Treatment with 10 mM metformin and 30 nM trametinib, a MEK inhibitor, was found to be effective in N-RAS mutant lung carcinomas, specifically SW1271 and H2347 cells.…”

“…Due to a high level of metastasis and post-surgical relapse, chemotherapy has become the most prevalent form of treatment. Unfortunately, cancer cells in general and lung cancer specifically are characterized by mutations and over activation of the PI3K-Akt-mTOR [17,18] and the Ras-MAPK [14,19] cascades that allow them to develop resistance to many first line chemotherapeutic agents highlighting the need to develop new chemotherapeutic agents.…”