Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

Fattore, Luigi; Ruggiero, Ciro Francesco; Pisanu, Maria Elena; Liguoro, Domenico; Cerri, Andrea; Costantini, Susan; Capone, Francesca; Acunzo, Mario; Romano, Giulia; Nigita, Giovanni; Mallardo, Domenico; Ragone, Concetta; Carriero, Maria Vincenza; Budillon, Alfredo; Botti, Gerardo; Ascierto, Paolo A.; Mancini, Rita; Ciliberto, Gennaro

doi:10.1038/s41418-018-0205-5

Cited by 55 publications

(83 citation statements)

References 49 publications

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“…In present treatments of cancers, the efficacy of single therapy is limited by the resistance produced in the host against such treatments . Hence, combinational therapy is necessary to enhance the therapeutic effectiveness of the cancer treatment .…”

Section: Introductionmentioning

confidence: 99%

Linear Chimeric Triblock Molecules Self‐Assembled Micelles with Controllably Transformable Property to Enhance Tumor Retention for Chemo‐Photodynamic Therapy of Breast Cancer

Yang

et al. 2019

Adv Funct Materials

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Although nanoparticles are expected to revolutionize cancer treatment, their low efficacy remains the greatest limiting factor. Recent investigations found that nanoparticles' golden principle, the enhanced permeability and retention (EPR) effect, is limited by the complicated tumor microenvironment. Herein, novel transformable nanomaterials are designed to utilize the EPR effect more effectively. By tandem conjugation of the hydrophobic head (chlorin e6 (Ce6) or bilirubin (BR)), peptide to form hydrogen bond (Phe-Phe-Val-Leu-Lys (FFVLK)), and hydrophilic tail (polyethylene glycol (PEG)), chimeric molecules that can form micelles (Ce6/BR-FFVLK-PEG) in aqueous solution are synthesized. Notably, the spherical micelles retain shape transformability. After circulation and distribution, they respond to 650 nm laser irradiation, and morphologically change into nanofibers so as to facilitate their retention markedly inside the tumor. Upon loading a reactive oxygen species-responsive paclitaxel dimer with thioketal linker (PTX 2 -TK), the resultant PTX 2 -TK@Ce6/BR-FFVLK-PEG nanomedicine serves as a potent chemo-photodynamic therapeutic for cancer treatment. Evaluations at both cell level and animal level reveal that PTX 2 -TK@Ce6/BR-FFVLK-PEG exhibits superior biocompatibility and biodistribution, and suppresses 82.6% of in vitro cell growth and 61.8% of in vivo tumor growth at a common dose of intravenous injection (10 mg kg −1 PTX and 3.3 mg kg −1 Ce6), becoming a novel nanomedicine with extraordinary potential in cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Linear Chimeric Triblock Molecules Self‐Assembled Micelles with Controllably Transformable Property to Enhance Tumor Retention for Chemo‐Photodynamic Therapy of Breast Cancer

Yang

et al. 2019

Adv Funct Materials

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“…Titer 96 AQueous One Solution Cell Proliferation Assay (Promega), according to the manufacturer's protocol. Colony formation assays have been performed by crystal violet staining as previously described (10).…”

Section: Methodsmentioning

confidence: 99%

Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

Fattore

Malpicci

Milite

et al. 2020

Preprint

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Abstract Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy.

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“…Towards this goal we first identified a novel oncosuppressor miRNA, miR-579-3p, as a novel master regulator of MAPKi resistance in BRAF-mutant melanoma patients [21]. Thereafter we carried out an intensive analysis of the entire miRnome before and after the establishment of in vitro resistance to BRAF inhibition [22]. This led to the identification of a set of 29 deregulated miRNAs which could be divided in miRNAs facilitators or antagonists of drug resistance, and whose expression allows to distinguish drug-sensitive from drug-resistant cells [22].…”

Section: Introductionmentioning

confidence: 99%

“…Thereafter we carried out an intensive analysis of the entire miRnome before and after the establishment of in vitro resistance to BRAF inhibition [22]. This led to the identification of a set of 29 deregulated miRNAs which could be divided in miRNAs facilitators or antagonists of drug resistance, and whose expression allows to distinguish drug-sensitive from drug-resistant cells [22]. In particular, we characterized in greater detail the biological activity of four additional miRNAs involved in the establishment of drug resistance, the two oncosuppressors miR-204-5p and miR-199b-5p and the two onco-miRs miR-4443 and miR-4488 [22].…”

Section: Introductionmentioning

confidence: 99%

“…This led to the identification of a set of 29 deregulated miRNAs which could be divided in miRNAs facilitators or antagonists of drug resistance, and whose expression allows to distinguish drug-sensitive from drug-resistant cells [22]. In particular, we characterized in greater detail the biological activity of four additional miRNAs involved in the establishment of drug resistance, the two oncosuppressors miR-204-5p and miR-199b-5p and the two onco-miRs miR-4443 and miR-4488 [22]. Through a combination of transfection studies or miRNA mimics or miRNA antagonists, we showed that these four microRNAs play an important role in drug resistance and affect in a positive or negative manner the efficacy of MAPKi based therapy [22].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Biophysical and Biological Characterization of Lipid Nanoparticles Co-Encapsulating Oncosuppressors miR-199b-5p and miR-204-5p as Potentiators of Target Therapy in Metastatic Melanoma

Fattore

Campani

Ruggiero

et al. 2020

IJMS

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Uncontrolled MAPK signaling is the main oncogenic driver in metastatic melanomas bearing mutations in BRAF kinase. These tumors are currently treated with the combination of BRAF/MEK inhibitors (MAPKi), but this therapy is plagued by drug resistance. In this context we recently discovered that several microRNAs are involved in the development of drug resistance. In particular miR-204-5p and miR-199b-5p were found to function as antagonists of resistance because their enforced overexpression is able to inhibit melanoma cell growth in vitro either alone or in combination with MAPKi. However, the use of miRNAs in therapy is hampered by their rapid degradation in serum and biological fluids, as well as by the poor intracellular uptake. Here, we developed lipid nanoparticles (LNPs) encapsulating miR-204-5p, miR-199b-5p individually or in combination. We obtained LNPs with mean diameters < 200 nm and high miRNA encapsulation efficiency. These formulations were tested in vitro on several melanoma cell lines sensitive to MAPKi or rendered drug resistant. Our results show that LNPs encapsulating combinations of the two oncosuppressor miRNAs are highly efficient in impairing melanoma cell proliferation and viability, affect key signaling pathways involved in melanoma cell survival, and potentiate the efficacy of drugs inhibiting BRAF and MEK. These results warrant further assessment of the anti-tumor efficacy of oncosuppressor miRNAs encapsulating LNPs in in vivo tumor models.

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Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

Cited by 55 publications

References 49 publications

Linear Chimeric Triblock Molecules Self‐Assembled Micelles with Controllably Transformable Property to Enhance Tumor Retention for Chemo‐Photodynamic Therapy of Breast Cancer

Linear Chimeric Triblock Molecules Self‐Assembled Micelles with Controllably Transformable Property to Enhance Tumor Retention for Chemo‐Photodynamic Therapy of Breast Cancer

Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

In Vitro Biophysical and Biological Characterization of Lipid Nanoparticles Co-Encapsulating Oncosuppressors miR-199b-5p and miR-204-5p as Potentiators of Target Therapy in Metastatic Melanoma

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