Synergistic targeted inhibition of <scp>MEK</scp> and dual <scp>PI</scp>3K/<scp>mTOR</scp> diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma

Wei, Bih‐Rong; Michael, Helen; Halsey, Charles; Peer, Cody J.; Adhikari, Amit S.; Dwyer, Jennifer E.; Hoover, Shelley; Meskini, Rajaâ El; Kozlov, Serguei; Ohler, Zoë Weaver; Figg, William D.; Merlino, Glenn; Simpson, R. Mark

doi:10.1111/pcmr.12512

Cited by 36 publications

(64 citation statements)

References 53 publications

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“…This was observed in both NF1 null and NF1 heterozygous cell lines, implying that they have potential therapeutic roles in NF1 ‐related nerve sheath tumours and sporadic MPNSTs, respectively, as well as SDMs. Similar synergistic inhibition with MEK inhibitors and mTORC1/2 inhibitors has been observed in models of canine melanoma cell lines . Currently, there are at least two phase Ib/II clinical trials aimed to test this combination of MEK + PI3K/mTOR inhibitors (NVP‐BEZ235 + MEK162) in a variety of resistant solid tumours (NCT#01337765 and NCT#01343498); the results of these studies have not been published.…”

Section: Discussionmentioning

confidence: 94%

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Jour¹,

Andeen

Al‐Rohil

et al. 2017

The Journal of Pathology

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Superficial malignant peripheral nerve sheath tumour (MPNST) is a rare, soft tissue neoplasm that shares morphological features and some molecular events with spindle/desmoplastic melanoma (SDM). Herein, we sought to identify molecular targets for therapy by using targeted RNA/DNA sequencing and gene expression of key immunological players. DNA and RNA from formalin-fixed paraffin-embedded tissue were extracted and processed.

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Section: Discussionmentioning

confidence: 94%

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Jour¹,

Andeen

Al‐Rohil

et al. 2017

The Journal of Pathology

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“…The phosphorylation of AKT can decrease this negative regulation, thus verifying that AKT aids in suppressing the negative regulatory factors of mTOR (25). However, more than one signaling pathway (other than PI3K/AKT) is responsible for the regulation of mTOR (26). Hunger and stress responses can result in the dephosphorylation of the autophagy-related protein Beclin-1, which inactivates mTOR and induces autophagy (26).…”

Section: Discussionmentioning

confidence: 91%

“…However, more than one signaling pathway (other than PI3K/AKT) is responsible for the regulation of mTOR (26). Hunger and stress responses can result in the dephosphorylation of the autophagy-related protein Beclin-1, which inactivates mTOR and induces autophagy (26). AKT can promote the activation of mTOR as an upstream effector molecule of mTORC1.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of miR-138 in patients with malignant melanoma through targeting of PDK1 in the PI3K/AKT autophagy signaling pathway

Meng

Zhang²,

et al. 2017

Oncology Reports

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The present study investigated the clinical significance of miR-138 in patients with malignant melanoma (MM), which has previously been associated with tumor growth. In patients with MM, we found that the expression of miR-138 was significantly downregulated when compared with healthy control subjects. Overexpression of miR-138 in the human melanoma cell line A2058 inhibited cell proliferation and induced cell apoptosis, and increased caspase-3 and Bax protein expression when compared with a negative control group. Meanwhile, miR-138 overexpression promoted cell autophagy, induced LC3 protein expression, and suppressed the PI3K/AKT/mTOR signaling pathway and PDK1 protein expression in A2058 cells. LY294002, an inhibitor of PI3K, suppressed PI3K/AKT/mTOR signaling, induced apoptosis, inhibited cell proliferation, increased caspase-3 and Bax protein expression, and decreased PDK1 protein expression in A2058 cells following miR-138 overexpression. Collectively, our findings indicate the clinical significance of miR-138 in patients with MM through its targeting of PDK1 expression in the PI3K/AKT/mTOR autophagy signaling pathway.

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“…These observations provide rational for a dual inhibitory strategy targeting both two signalings. Some preclinical studies have already shown that a combination of mTOR inhibitors with inhibitors targeting MEK or Raf leds to an enhanced response (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

The Altered Metabolic Molecular Signatures Contribute to the RAD001 Resistance in Gastric Neuroendocrine Tumor

Pan

Bao

Enders³

2020

Front. Oncol.

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Although the inhibition of mTOR is a promising treatment for neuroendocrine tumors, several questions are still open for cell specificity and resistance. With the newly characterized gastric neuroendocrine tumor mouse model (CEA424-SV40 T antigen transgenic mice), the anti-tumor efficiency of RAD001 (Everolimus) was tested both in vitro and in vivo. Tumor samples were analyzed for the expression of RNA by cDNA microarrays and also signaling pathways to get more details on the local surviving or selected cells. RAD001 treatment dramatically slowed down tumor growth and prolonged the animals' survival. This inhibitory effect has a preference for tumor cells since gastrointestinal hormone and neuroendocrine tumor specific markers were more reduced than the epithelial ones. While phosphorylation of p70S6K was almost completely blocked both in vitro and in vivo, the phosphorylation of 4EBP1 was only partially inhibited in vitro and unaffected in vivo. RAD001 treatment induced feedback activation of metabolism related pathways like PI(3)K-Akt-mTOR and MEK/ERK signalings. An induction of senescence as well as differential expression of genes responsible for metabolism was also observed, which highlighted the contribution of metabolic molecular signatures to the escape of the tumor cells from the treatment. Together, our data revealed efficient anti-tumor ability of RAD001 in a new gastric neuroendocrine tumor mouse model system and offered new insights into the clinical aspects of the incomplete elimination of tumor cells in patients treated.

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Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma

Cited by 36 publications

References 53 publications

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Clinical significance of miR-138 in patients with malignant melanoma through targeting of PDK1 in the PI3K/AKT autophagy signaling pathway

The Altered Metabolic Molecular Signatures Contribute to the RAD001 Resistance in Gastric Neuroendocrine Tumor

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