In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTEN(LOF)/BRAF(MUT) melanoma.
Downregulation of FOXM1 by siRNA significantly inhibited the proliferation of melanoma cells, and blockade of the MAPK and PI3K/AKT pathways decreased the FOXM1 expression in melanoma cell lines.
These results suggest that intrinsic resistance to BRAF inhibition is frequently associated with primary cross-resistance to MEK and PI3K/mTOR blockade in BRAF-mutant melanoma and provide pre-clinical evidence for a combinatorial approach to counteract this phenotype.
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.
Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma.
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.
Through this route, we confirmed Rapamycin as a compound that could synergize with MEKi and even more so with PI3K/mTORi to suppress melanoma development, including suppressing the growth of cultured human melanoma cells.
Current genetically-engineered mouse melanoma models are often based on <i>Tyr::CreER<sup>T2</sup></i>-controlled MAPK pathway activation by the BRAF<sup>V600E</sup> mutation and PI3K pathway activation by loss of PTEN.
Although PI3K inhibition resulted in cytostatic effects on xenografted NRAS<sup>Q61H</sup> /PIK3CA<sup>H1047R</sup> melanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression.
Finally, we describe findings of high translational significance by demonstrating that Abl/Arg cooperate with PI3K/Akt/PTEN, a parallel pathway that is associated with intrinsic resistance to BRAFi and immunotherapy, as Abl/Arg and Akt inhibitors cooperate to prevent viability, cell cycle progression and in vivo growth of melanomas harboring mutant BRAF/PTEN.
Our data indicate that in mucosal melanomas RAS/NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors.
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.
Mutations in EGFR, KRAS, BRAF, and PIK3CA genes are widely analyzed in solid tumors such as lung cancer, colorectal cancer, breast cancer, and melanoma.
The mitogen‑activated protein kinase (MAPK) pathway, phosphoinositol‑3‑kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways.
In this study, we found that Ashitaba (<i>Angelica keiskei</i>) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma development by directly targeting both BRAFV600E and PI3K, which blocked the activation of downstream signaling.
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.
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.
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.