Joint action of miR‐126 and MAPK/PI3K inhibitors against metastatic melanoma

Abstract

Emerging data support the rationale of combined therapies in advanced melanoma. Specifically, the combined use of drugs with different mechanisms of action can reduce the probability of selecting resistant clones. To identify agents active against melanoma cells, we screened a library of 349 anti‐cancer compounds, currently in clinical use or trials, and selected PIK ‐75, an inhibitor of the phosphatidylinositol 3‐kinase/protein kinase B ( PI 3K/ AKT ) pathway, as the ‘top active’ drug. PIK ‐75 was then used alone or in combination with vemurafenib, the first BRAF inhibitor approved for patients with melanoma harboring BRAF mutations. We identified a combined dose of PIK ‐75 and vemurafenib that inhibited both the PI 3K/ AKT and mitogen‐activated protein kinase pathways, thereby overcoming any compensatory activation. In view of the important tumor suppressor function induced by restoring expression of microRNA (miR)‐126 in metastatic melanoma cells, we examined whether miR‐126 has a synergistic role when included in a triple combination alongside PIK ‐75 and vemurafenib. We found that enforced expression of miR‐126 (which alone can reduce tumorigenicity) significantly increased PIK ‐75 activity when used as either a single agent or in combination with vemurafenib. Interestingly, PIK ‐75 proved to be effective against early passage cell lines derived from patients’ biopsies and on melanoma cell lines resistant to either vemurafenib or dabrafenib, thus suggesting that it potentially has the capability to overcome drug resistance. Finally, the synergistic role played by miR‐126 in combination with vemurafenib and/or PIK ‐75 was demonstrated in vivo in mouse xenograft models, in which tumor growth inhibition was associated with increased apoptosis. These results not only show the efficacy of PIK ‐75 and vemurafenib co‐treatment but also indicate that restoration of miR‐126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits.

The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer

“…For example, the effect of simvastatin on the repression of cell survival and metastasis is enhanced by the combined inhibition of miR-21 [ 278 ]. Also, miR-126-3p reconstitution synergistically improves the combinatorial effects of PIK-75 with vemurafenib on apoptotic cell death in vivo [ 279 ]. In addition, lncRNA-TCL6 overexpression can potentiate the rate of apoptotic cell death induced by paclitaxel [ 280 ].…”

Resistance to Molecularly Targeted Therapies in Melanoma

“…One study using uveal melanoma cells showed near complete inhibition of cell proliferation in cells treated with LY294002, as well as increased efficacy of LY294002 when combined with rapamycin [ 36 ]. Further studies have found that a combined dose of PIK-75 and vemurafenib, a BRAF inhibitor, halts both the PI3K/AKT and mitogen-activated protein kinase pathways, which proved to be effective against early passage cell lines derived from patient tumor samples and on melanoma cell lines resistant to either vemurafenib or dabrafenib [ 225 ]. These experiments confirm the expected effects on key signaling pathways, demonstrating the crosstalk between PI3K/AKT and MAPK pathways [ 225 ].…”

Overcoming Compensatory Mechanisms toward Chronic Drug Administration to Ensure Long-Term, Sustainable Beneficial Effects

“…miR-126 has a synergistic role in overcoming resistance when included in a triple combination alongside PIK-75 and vemurafenib. 26 The receptor tyrosine kinase, MET, is upregulated or over-activated in glioblastoma (GBM). Resistance to anti-MET drugs frequently occurs.…”