Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma

Shannan, Batool; Matschke, Johann; Chauvistré, Heike; Vogel, Felix C. E.; Klein, Diana; Meier, Friedegund; Westphal, Dana; Bruns, Johannes; Rauschenberg, Ricarda; Utikal, Jochen; Forschner, Andrea; Berking, Carola; Terheyden, Patrick; Dabrowski, Evelyn; Gutzmer, Ralf; Rafei-Shamsabadi, David; Meiß, Frank; Heinzerling, Lucie; Zimmer, Lisa; Livingstone, Elisabeth; Váraljai, Renáta; Hoewner, A.; Horn, Susanne; Klode, Joachim; Stuschke, Martin; Scheffler, Björn; Marchetto, Aruna; Sannino, Giuseppina; Grünewald, Thomas G.P.; Schadendorf, Dirk; Jendrossek, Verena; Roesch, Alexander

doi:10.1016/j.ejca.2018.12.024

Cited by 20 publications

(11 citation statements)

References 43 publications

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“…Also, single symptomatic metastases can be irradiated if systemic treatment controls disease in the rest of the body. In recent years, targeted therapies such as BRAFMEK inhibitor therapy and immune check point inhibitors with anti-CTLA4/PD-1 antibodies have improved the overall survival of patients with metastatic melanoma [48,49] and the combination of radiotherapy with systemic therapies has been thoroughly evaluated [50][51][52][53]. Nevertheless, outcomes are still dissatisfying, and improvement is required.…”

Section: Introductionmentioning

confidence: 99%

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential

Bürkel

Jost

Hecht

et al. 2020

IJMS

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CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC-115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.

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Section: Introductionmentioning

confidence: 99%

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential

Bürkel

Jost

Hecht

et al. 2020

IJMS

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“…Shannan et al. displayed that KDM5B favored cell survival by transcriptional modulation of genes related to cell cycle, DNA repair and cell death [ 31 ]. Our observations derived from rescue experiments exhibited that silencing of PIK3C3 mitigated the effects of sh-KDM5B on ESCC cell autophagosome formation, cell cycle arrest, and radio-resistance.…”

Section: Discussionmentioning

confidence: 99%

Overcoming radio-resistance in esophageal squamous cell carcinoma via hypermethylation of PIK3C3 promoter region mediated by KDM5B loss

Wang

et al. 2022

Journal of Radiation Research

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Many patients with esophageal squamous cell carcinoma (ESCC) are inoperable because of old age or the advanced stage of the disease; thus radio- and chemotherapy are believed as the standard treatments for these patients. However, due to the radio-resistance of tumor cells that may develop during radiotherapy, results remain unsatisfactory. In this article, the possible relationship between the expression of lysine demethylase 5B (KDM5B) and ESCC radio-resistance is clarified, and the underlying mechanism is evaluated. Using the GSE75241 microarray, we identified KDM5B as a potential oncogene in ESCC. KDM5B was overexpressed in ESCC patients and cells. Inhibition of KDM5B enhanced the H3K4me3 methylation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) promoter and induced the expression of PIK3C3. Knockdown of KDM5B or overexpression of PIK3C3 in KYSE-150 and TE-10 cells promoted apoptosis, cell cycle arrest, autophagy, and increased sensitivity to radiotherapy. Silencing of PIK3C3 attenuated the promoting effect of sh-KDM5B on the sensitivity of ESCC cells to radiotherapy. The inhibition of sh-KDM5B in radio-resistance of ESCC cells was also reproduced in vivo. Taken together, our findings provide evidence that reduced expression of KDM5B has a critical role in promoting ESCC radio-sensitivity by upregulating PIK3C3, suggesting KDM5B may function as an oncogene in ESCC.

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“…The following human melanoma cell lines were maintained in 2% FBS-substituted (Tu2% 32 ) or 4% FBS-substituted (Tu4% 33 melanoma medium at 5% CO2: Wistar cell lines 451Lu ( BRAF V 600 E , PTEN wt , NRAS wt ), 451Lu BR ( BRAF V600E , PTEN wt , NRAS wt ), WM164 ( BRAF V600E , PTEN wt , NRAS wt ), WM3734 ( BRAF V600E , PTEN del , NRAS wt ), WM88 ( BRAF V600E , PTEN wt , NRAS wt ), WM9 ( BRAF V600E , PTEN del , NRAS wt ), WM983B ( BRAF V600E , PTEN wt , NRAS wt ), WM983B BR ( BRAF V600E , PTEN wt , NRAS wt ). Details on WM3734 KDM5Bprom-EGFP , lentiviral infected WM3734_sh_KDM5B_62 and WM3734_sh_scramble control cells and WM3734 Tet3G-shJARID1B were previously described 15, 34 . The commercial human melanoma cell lines MelJuSo ( BRAF WT , PTEN WT , NRAS NRASQ61L ), MeWo ( BRAF WT , PTEN WT , NRAS wt ), SKMel5 ( BRAF V600E , PTEN n.d. , NRAS wt ), SKMel28 ( BRAF V600E , PTEN T167A , NRAS wt ) were grown in RPMI medium with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Persister state-directed transitioning and vulnerability in melanoma

Chauvistré

Shannan

Daignault

et al. 2020

Preprint

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Phenotypic intratumoral heterogeneity and temporal transitions between cell differentiation states represent major drivers of tumor fitness in melanoma. Expression of the histone H3K4 demethylase KDM5B/JARID1B follows a highly dynamic equilibrium across melanoma cells.When challenged for example with targeted or cytotoxic drugs, the intrinsically slow-cycling KDM5B high cell state becomes initially enriched, whereas under persistent drug-exposure melanomas decrease KDM5B expression again to re-enter cell proliferation for long-term tumor repopulation. However, the exact role of KDM5B for tumor cell differentiation and fate remained elusive so far. Here, we show that melanoma fitness can be overcome by molecular enforcement of high KDM5B expression levels. KDM5B-up-scaled melanoma cells are transcriptionally reprogramed towards a differentiated melanocytic profile including a slowcycling state. This effect can be phenocopied by a newly identified chemical compound also leading to decelerated tumor growth. Mechanistically, KDM5B represents a checkpoint for coordinating the differentiation phenotype of melanoma cells via transcriptional reprograming, cell cycle delay, and attenuation of cytokinetic abscission. These findings indicate that tumor plasticity per se, i.e. the necessity of cancer cells to dynamically switch between different cell cycling and differentiation states, represents an important oncologic process that can be chemically overcome.

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Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma

Cited by 20 publications

References 43 publications

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential

Overcoming radio-resistance in esophageal squamous cell carcinoma via hypermethylation of PIK3C3 promoter region mediated by KDM5B loss

Persister state-directed transitioning and vulnerability in melanoma

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