PIM kinases as therapeutic targets against advanced melanoma

Shannan, Batool; Watters, Andrea; Chen, Quan; Mollin, Stefan; Dörr, Markus; Meggers, Eric; Xu, Xiaowei; Gimotty, Phyllis A.; Perego, Michela; Li, Ling; Benci, Joseph L.; Krepler, Clemens; Brafford, Patricia; Zhang, Jie; Wei, Zhi; Zhang, Gao; Liu, Qin; Yin, Xiangfan; Nathanson, Katherine L.; Herlyn, Meenhard; Vultur, Adina

doi:10.18632/oncotarget.10703

Cited by 17 publications

(12 citation statements)

References 52 publications

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“…One of the major problems in the treatment of melanoma with BRAFi or BRAFi þ MEKi is the development of resistance. We evaluated the effect of PLX4720 on M6PR expression in BRAFresistant cell lines generated by long-term exposure to increased concentrations of inhibitors that has been described previously (30). Cell lines resistant to BRAFi or to combination of BRAFi and MEKi showed increased (P ¼ 0.02) expression of M6PR as compared with untreated cell lines ( Supplementary Fig.…”

Section: Plx4720 Treatment Causes Upregulation Of M6pr In Plx4720resimentioning

confidence: 99%

BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

Atay

Kwak

Lavilla-Alonso

et al. 2019

Clinical Cancer Research

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Purpose: BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAF V600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi.Experimental Design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT.Results: Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment.Conclusions: BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.

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Section: Plx4720 Treatment Causes Upregulation Of M6pr In Plx4720resimentioning

confidence: 99%

BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

Atay

Kwak

Lavilla-Alonso

et al. 2019

Clinical Cancer Research

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“…PIM kinases (a family of Ser/Thr kinases) promotes proliferation and progression of cancer cell [ 17 ]. Our previous study showed that upregulation of Pim1 promotes hepatocarcinogenesis through PKM2 and CUDR [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

HistoneH3 demethylase JMJD2A promotes growth of liver cancer cells through up-regulating miR372

Jiao

Song

et al. 2017

Oncotarget

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Changes in histone lysine methylation status have been observed during cancer formation. JMJD2A protein is a demethylase that is overexpressed in several tumors. Herein, our results demonstrate that JMJD2A accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, JMJD2A promoted the expression and mature of pre-miR372 epigenetically. Notably, miR372 blocks the editing of 13th exon-introns-14th exon and forms a novel transcript(JMJD2AΔ) of JMJD2A. In particular, JMJD2A inhibited P21(WAF1/Cip1) expression by decreasing H3K9me3 dependent on JMJD2AΔ. Thereby, JMJD2A could enhance Pim1 transcription by suppressing P21(WAF1/Cip1). Furthermore, through increasing the expression of Pim1, JMJD2A could facilitate the interaction among pRB, CDK2 and CyclinE which prompts the transcription and translation of oncogenic C-myc. Strikingly, JMJD2A may trigger the demethylation of Pim1. On the other hand, Pim1 knockdown and P21(WAF1/Cip1) overexpression fully abrogated the oncogenic function of JMJD2A. Our observations suggest that JMJD2A promotes liver cancer cell cycle progress through JMJD2A-miR372-JMJD2AΔ-P21WAF1/Cip1-Pim1-pRB-CDK2-CyclinE-C-myc axis. This study elucidates a novel mechanism for JMJD2A in liver cancer cells and suggests that JMJD2A can be used as a novel therapeutic targets of liver cancer.

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“…A growing body of evidence has demonstrated that atopic expression of PIM-1 in cancer cells is responsible for tumour growth and metastasis [3]. Inhibition of PIM-1 by knockdown studies can reduce proliferation and viability in preclinical models of melanoma [4]. However, the exact role of PIM-1 as a therapeutic target in melanoma is not clearly understood.…”

Section: Pim-1 Which Belongs To the Pim Family Is -----------------mentioning

confidence: 99%

Inhibition of autophagy enhances SMI-4a-induced growth inhibition and apoptosis of melanoma cells

Chen¹,

Lv²,

Liu³

et al. 2018

Trop. J. Pharm Res

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Purpose: To investigate the exact role of the proviral integration site for Moloney murine leukemia virus-1 (PIM-1) on autophagy as well as the underlying molecular mechanisms in melanoma. Methods: mRNA expression levels in A375 and G361 human melanoma cell lines were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent (ELISA) and western blotting assays were applied to determine protein expression levels, while cell viability was evaluated using Cell Counting Kit 8 and colony formation assay. Flow cytometric analysis and caspase 3/7 activity assay were used to assess apoptosis. Results: The results show that pharmacological inhibition of PIM-1 with its potent inhibitor (SMI-4a) suppressed cell viability and induced apoptosis in melanoma cell lines A375 and G361. SMI-4a also induced autophagy through inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis in melanoma cells

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PIM kinases as therapeutic targets against advanced melanoma

Cited by 17 publications

References 52 publications

BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells

HistoneH3 demethylase JMJD2A promotes growth of liver cancer cells through up-regulating miR372

Inhibition of autophagy enhances SMI-4a-induced growth inhibition and apoptosis of melanoma cells

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