Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors

Abstract

Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.

Bioinformatics Analysis of Global Proteomic and Phosphoproteomic Data Sets Revealed Activation of NEK2 and AURKA in Cancers

“…Thus, an extensive research is striding to identify the inhibitors for the kinases with increased activity for better clinical outcome and cancer management. Several families of kinases, such as tyrosine kinases [14], cycle-dependent kinases [15][16][17], aurora kinases [17,18], mTOR [19], and mitogen-activated protein kinases [20] already have FDA approved inhibitors, which are at different phases of clinical trials. Large profiling data sets have proved to be immensely useful for translational research in the area of cancer treatment.…”

Current Advances in the Treatment of BRAF-Mutant Melanoma

“…These have emerged as alternative treatment options for treating metastatic melanoma patients. Preclinical and clinical trials evaluating the efficacy of various PI3K and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are also initiated [17][18][19][20][21][22].…”

HOXC10 promotes growth and migration of melanoma by regulating Slug to activate the YAP/TAZ signaling pathway

“…In the past decade, scholars have conducted a large number of researches and clinical trials to explore the potential molecular pathogenesis and treatment strategies of melanoma. At present, it has been proved that there are various pathways are associated with the occurrence of melanoma, such as MAPK, PI3K/Akt and YAP/TAZ pathways [5][6][7][8].…”