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Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance.

ABSTRACT: BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients.

SUBMITTER: Fattore L

PROVIDER: S-EPMC9684877 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance.

Fattore Luigi L Cafaro Giordana G Di Martile Marta M Campani Virginia V Sacconi Andrea A Liguoro Domenico D Marra Emanuele E Bruschini Sara S Stoppoloni Daniela D Cirombella Roberto R De Nicola Francesca F Pallocca Matteo M Ruggiero Ciro F CF Castaldo Vittorio V Catizone Angiolina A Del Bufalo Donatella D Viglietto Giuseppe G Vecchione Andrea A Blandino Giovanni G Aurisicchio Luigi L Fanciulli Maurizio M Ascierto Paolo A PA De Rosa Giuseppe G Mancini Rita R Ciliberto Gennaro G

Oncogene 20221123 4

BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of the ...[more]

PMID: 36418472

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Project description:BackgroundThe Food and Drug Administration has approved the Serine/threonine-protein kinase B-raf (BRAF) inhibitor and Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor combo as the first-line treatment for individuals with metastatic melanoma, although the majority of these patients exhibit primary or secondary drug resistance in the clinic. Dihydrotanshinone I (DHT) is a lipophilic compound extracted from the root of Salvia miltiorrhiza that has been linked to multiple antitumor activities. In this study, we investigated the effect of dihydrotanshinone I on the MAPK pathway inhibitor resistance of BRAF mutant malignant melanoma.MethodAfter treating A375, A375R, and A2058 cells with DHT or a combination of DHT and BRAF/MEK inhibitors, WB and Real-Time RT-qPCR were used to confirm the activation of the MAPK and STAT3/SOX2 pathways. CCK-8 was used to assess cell viability, while flow cytometry was used to identify apoptosis. In addition, mice were inoculated with A375 cells to establish a model of tumour formation, and various drug groups and treatment models were utilized. The diameter and weight of tumours in each group were then measured, and IHC and HE staining were used to assess the expression of two pathways and cytotoxicity, respectively.ResultsThis study found that DHT directly interacts with STAT3 protein and it can stop the feedback activation of the STAT3/SOX2 pathway caused by the use of MAPK pathway inhibitors. In addition, the combination of DHT and BRAF/MEK inhibitors can inhibit the proliferation and growth of BRAF mutant melanoma cells and primary and secondary drug-resistant cells. Finally, we proved that the combined therapy of DHT and BRAF/MEK inhibitors is reliable and effective at animal and cell levels.ConclusionIn BRAF mutant melanoma cells, DHT suppresses the STAT3/SOX2 signaling pathway. Combining DHT, BRAF inhibitors, and MEK inhibitors can help treat treatment-resistant BRAF mutant melanoma cells. Experimental results both in vitro and in vivo have shown that the combination of DHT and an inhibitor of the MAPK pathway is safer and more successful than using an inhibitor of the MAPK pathway alone when treating BRAF mutant melanoma.

Dataset Information

Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance.

Publications

Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance.

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