Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition

Makino, Elena; Fröhlich, Lisa Marie; Sinnberg, Tobias; Kosnopfel, Corinna; Sauer, Birgit; Garbe, Claus; Schittek, Birgit

doi:10.1038/s41419-020-2702-y

Cited by 15 publications

(32 citation statements)

References 49 publications

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“…Downregulated levels of TAp73alfa resulted in reduced NER capacity in melanoma cells and enhanced susceptibility to DNA cross-linking agents as consequences of accumulating DNA damage [ 40 ]. Moreover, it was found that drug-resistant melanoma cells rely on RAD51 expression for survival and can be successfully targeted with Rad51 inhibitors [ 33 ]. Rad51 is an indispensable protein of the homology-directed DNA repair pathway and is critical for the maintenance of genomic stability [ 7 ].…”

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

“…Rad51 is an indispensable protein of the homology-directed DNA repair pathway and is critical for the maintenance of genomic stability [ 7 ]. Its expression in melanoma cells is in part regulated by Elk1 as an outlet of MAPK signaling [ 33 , 130 ]. Inhibition of RAD51 led to the accumulation of DNA damage and enhanced drug efficacy in drug-naïve, vemurafenib-resistant and vemurafenib and trametinib double-resistant melanoma cells, as well as in a xenograft of melanoma cells isolated from a patient with developed resistance to vemurafenib [ 33 ].…”

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

“…Its expression in melanoma cells is in part regulated by Elk1 as an outlet of MAPK signaling [ 33 , 130 ]. Inhibition of RAD51 led to the accumulation of DNA damage and enhanced drug efficacy in drug-naïve, vemurafenib-resistant and vemurafenib and trametinib double-resistant melanoma cells, as well as in a xenograft of melanoma cells isolated from a patient with developed resistance to vemurafenib [ 33 ]. Notably, Rad51 inhibitors showed no apparent toxicity in mice, which warrants further research into clinical application of Rad51 inhibitors in the treatment of cancers, including melanoma [ 33 ].…”

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

“…Inhibition of RAD51 led to the accumulation of DNA damage and enhanced drug efficacy in drug-naïve, vemurafenib-resistant and vemurafenib and trametinib double-resistant melanoma cells, as well as in a xenograft of melanoma cells isolated from a patient with developed resistance to vemurafenib [ 33 ]. Notably, Rad51 inhibitors showed no apparent toxicity in mice, which warrants further research into clinical application of Rad51 inhibitors in the treatment of cancers, including melanoma [ 33 ]. Drug-resistant melanoma cells have also been shown to lose phosphatase and tensin homolog (PTEN) expression to maintain the pro-survival signaling of the PI3K/AKT pathway [ 131 , 132 ].…”

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

“…Somewhat surprisingly, despite the immense frequency of genetic alterations in melanoma, it is not associated with somatic defects in DNA repair [ 32 ]. On the contrary, melanomas overexpress some of the elements of the DNA repair machinery [ 33 ]. Furthermore, the ability of melanoma cells to give rise to distant metastases may rely on a certain level of genetic stability, as evidenced by increased expression of DNA repair associated genes in metastatic tumors, compared to primary lesions [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Genome Stability in Melanoma—A New Approach to an Old Field

Osrodek

Wozniak

2021

IJMS

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Despite recent groundbreaking advances in the treatment of cutaneous melanoma, it remains one of the most treatment-resistant malignancies. Due to resistance to conventional chemotherapy, the therapeutic focus has shifted away from aiming at melanoma genome stability in favor of molecularly targeted therapies. Inhibitors of the RAS/RAF/MEK/ERK (MAPK) pathway significantly slow disease progression. However, long-term clinical benefit is rare due to rapid development of drug resistance. In contrast, immune checkpoint inhibitors provide exceptionally durable responses, but only in a limited number of patients. It has been increasingly recognized that melanoma cells rely on efficient DNA repair for survival upon drug treatment, and that genome instability increases the efficacy of both MAPK inhibitors and immunotherapy. In this review, we discuss recent developments in the field of melanoma research which indicate that targeting genome stability of melanoma cells may serve as a powerful strategy to maximize the efficacy of currently available therapeutics.

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Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

Section: Mitogen-activated Protein Kinase Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Genome Stability in Melanoma—A New Approach to an Old Field

Osrodek

Wozniak

2021

IJMS

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PARP1 expression predicts PARP inhibitor sensitivity and correlates with metastatic potential and overall survival in melanoma

Fröhlich,

Villar‐Miyar,

Heintze

et al. 2024

Intl Journal of Cancer

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Metastatic melanoma is still a difficult‐to‐treat cancer type owing to its frequent resistance mechanisms to targeted and immunotherapy. Therefore, we aimed to unravel novel therapeutic strategies for melanoma patients. Preclinical and clinical studies show that melanoma patients may benefit from a treatment with poly (ADP‐ribose) polymerase (PARP) inhibitors (PARPi). In this study, we focus on PARP1 as a potential biomarker to predict the response of melanoma cells to PARPi therapy. We found that melanoma cells with high basal PARP1 expression exhibit significantly increased cell death after PARPi treatment owing to higher PARP1 trapping compared with melanoma cells with low PARP1 expression. In addition, we could demonstrate that PARP1 expression levels are low in nonmalignant skin cells, and metastatic melanomas show considerably higher PARP1 levels compared with primary melanomas. Most strikingly, we found that high PARP1 levels correlate with worse overall survival of late stage metastasized melanoma patients. In conclusion, we show that PARP1 might act as a biomarker to predict the response to PARPi therapy, and that in particular the late stage metastasized melanoma patients are especially sensitive to PARPi therapy owing to elevated PARP1 expression. Our data suggest that the PARPi cytotoxicity primarily will affect the high PARP1 expressing melanoma cells, rather than the low PARP1 expressing nonmalignant skin cells resulting in only low side effects.

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Targeting DNA repair to enhance the efficacy of sorafenib in hepatocellular carcinoma

Samadaei

Senfter

Madlener

et al. 2022

J of Cellular Biochemistry

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The multityrosine kinase inhibitor sorafenib remains an important systemic treatment option for hepatocellular carcinoma (HCC). Signaling pathways, which are targeted by sorafenib, are involved in checkpoint and DNA repair response, RAD51 being a candidate protein. Here, we aim to evaluate the effect of the human RAD51 inhibitor B02 in combination with sorafenib in human HCC cells. Impact of RAD51 expression on HCC patient survival was evaluated by an in silico approach using Human Protein Atlas dataset. Cell viability of HUH7, AKH12, AKH13, and 3P was assessed by neutral red assay. To measure the cytotoxicity, we quantified loss of membrane integrity by lactate dehydrogenase release. We also employed colony formation assay and hanging drop method to assess clonogenic and invasive ability of HCC cell lines upon sorafenib and B02 treatment. Cell cycle distribution and characterization of apoptosis was evaluated by flow cytometry. In silico approach revealed that HCC patients with higher expression of RAD51 messenger RNA had a significantly shorter overall survival. The RAD51 inhibitor B02 alone and in combination with sorafenib significantly reduced viability, colony formation ability, and invasion capacity of HCC cells. Cell cycle analysis revealed that the combination of both agents reduces the proportion of cells in the G2/M phase while leading to an accumulating in the subG1 phase. The RAD51 inhibitor B02 seems to be a promising agent for HCC treatment and enhances the antitumor effects of sorafenib in vitro.

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Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition

Cited by 15 publications

References 49 publications

Targeting Genome Stability in Melanoma—A New Approach to an Old Field

Targeting Genome Stability in Melanoma—A New Approach to an Old Field

PARP1 expression predicts PARP inhibitor sensitivity and correlates with metastatic potential and overall survival in melanoma

Targeting DNA repair to enhance the efficacy of sorafenib in hepatocellular carcinoma

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