Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.
In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades.
The most promising include: i) vertical targeting of either MEK or phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways, or their combined blockade; ii) association of receptor tyrosine kinases (RTKs) inhibitors with other pro-apoptotic strategies; iii) engagement of death receptors in combination with MEK-, mTOR/PI3K-, histone deacetylase (HDAC)-inhibitors, or with anti-apoptotic molecules modulators; iv) strategies aimed at blocking anti-apoptotic proteins belonging to B-cell lymphoma (Bcl-2) or inhibitors of apoptosis (IAP) families associated with MEK/BRAF/p38 inhibition; v) co-inhibition of other molecules important for survival [proteasome, HDAC and Signal transducers and activators of transcription (Stat)3] and the major pathways activated in melanoma; vi) simultaneous targeting of multiple anti-apoptotic molecules.
Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance.
These results demonstrate that the combination of HSP90 and PI3K/mTOR inhibitors could be an effective therapeutic strategy that target the main survival pathways in melanoma and must be considered to overcome resistance to BRAF inhibitors in melanoma patients.
Among the possible targets in melanoma are the Ras-MAPK and PI3K/AKT signal transduction pathways, the proteasome, histone deacetylases, methyltransferases, and melanoma-induced angiogenesis.
Herein, we examined whether targeting the RAS-RAF-MEK-ERK pathway with the RAF inhibitor sorafenib and/or the PI3K-AKT-mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma.
The phosphoinositide-3 kinase (PI3K) pathway is deregulated in a significant proportion of melanomas, and PI3K pathway activation in combination with constitutively active mitogen-activated protein kinase signaling shows synergistic effects in the process of melanoma tumorigenesis.
We demonstrate that SAR260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models, and has synergistic antitumor activity when combined with vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models.
Collectively, our results indicated that Lyn plays a carcinogenic role in multiple cellular functions during melanoma development through regulating apoptosis and autophagy via the PI3K/Akt pathway and may be a valuable potential target for the clinical treatment of melanoma.
Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas.
We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner.
Thus, the concurrent inhibition of PI3K and MAPK signalling is required to suppress oncogenic c-Kit activity and may provide an effective therapeutic strategy in c-Kit mutant melanomas.
However, PI3K pathway mutations, though more heterogeneous, were present in 41% of the melanoma, with PTEN being the highest mutated PI3K gene in melanomas (22%).
Functional analyses of differentially expressed genes (DEGs), obtained from the GEO (Gene Expression Omnibus) database, indicated that high proliferative and metastatic abilities are the main characteristics of melanoma and that the PI3K and MAPK pathways play essential roles in melanoma progression.
Thus, this study details the development of selenocoxib-1-GSH, which is a nontoxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development.
In conclusion, our study demonstrated that SCH-527123, a small-molecule antagonist for CXCR1 and CXCR2 inhibited cell proliferation, migration and invasion in melanoma via PI3K/AKT pathway.