In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.
BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer.
In this issue of <i>Science Signaling</i>, Yuan <i>et al.</i> report that MEK1 homodimerization is necessary for signal transduction through the RAF-ERK pathway and that cancer-related MEK1 mutations confer enhanced dimerization and resistance to MEK inhibitors.
Several of these hypermethylated CpG islands are associated with genes involved in the MEK-ERK pathway, one of the most frequently disrupted pathways in cancer.
The Ras-Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase/mitogen-activated protein kinase (Ras-Raf-MEK-ERK/MAPK) signaling pathway is at the heart of the signaling networks that control many fundamental cellular processes and Raf kinases takes centre stage in the MAPK pathway, which is now appreciated to be one of the most common sources of the oncogenic mutations in cancer.
Moreover, the Ras/Raf/MEK/ERK pathway has been estimated to be mutated in 30% of all cancers, thus making it the focus of many scientific studies which have lead to a deeper understanding of cancer development and help to elucidate potential weaknesses that can be targeted by pharmacological agents [1].
Two isoforms of extracellular regulated kinase (ERK), namely ERK-1 and ERK-2, are associated with several cellular processes, the aberration of which leads to cancer.
Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata.
Experimental results on male BALB/c nude mice confirmed that orally administration of COP at high-dose (150 mg/kg) could suppress tumor growth, and may reduce cancer metastasis risk by inhibiting the RAS-ERK pathway in vivo.
Additionally, mutations in protein phosphatase 2 regulatory subunit α (PPP2R1A), ring finger protein 43 (RNF43), DNA directed polymerase ε (POLE1), ribonuclease type III (DICER1), CCCTC‑binding factor (CTCF), ribosomal protein L22 (RPL22), DNA methyltransferase 3α (DNMT3A), transformation/transcription domain‑associated protein (TRRAP), isocitrate dehydrogenase (IDH)1 and IDH2 were not detected in ovarian mixed germ cell tumors, implicating these genetic alterations may be not associated with MAPK1 mutation in the development of this malignancy.
In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer.
Notably, a most prevalent B-Raf(v600e) mutant in Raf kinase family exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy.
Knockdown of BMPR1a of breast cancer cells suppresses their production of RANKL via p38 pathway and inhibits cancer-induced osteoclastogenesis, which indicates that BMPR1a might be a possible target in breast cancer-induced osteolytic metastasis.
Therefore, the identification of Ras-ERK/MAPK signaling pathway-associated regulators is critical to understand the mechanism of stem cell (possibly cancer stem cell) control.
Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways.
Signalling through the ERK MAP kinase pathway plays an important role in many biological processes and it is often deregulated in disease states such as cancer.
The observation that both MAPK and Bcl-2/Bax signaling play a central role in the pathogenesis of human cancer suggests that this kinase cascade represents a novel opportunity for the development of new anticancer targeted therapies designed to be less toxic than conventional chemotherapy.
Altogether, our findings indicate that high expression of GAL1 is associated with distant metastasis of OS patients, and knockdown of GAL1 inhibits growth and invasion of OS cells possibly through inhibition of the MAPK/ERK pathway, suggesting that GAL1 may represent a potential target for the treatment of cancer.
Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.