bims-myxlip 2021-09-26 papers

Issue of 2021–09–26
two papers selected by
Laura Mannarino, Humanitas Research

Mol Cancer Ther. 2021 Sep 22. pii: molcanther.0315.2021. [Epub ahead of print]

Predictive value of MRP-1 in localized high-risk soft tissue sarcomas: a translational research associated to ISG-STS 1001 randomized phase III trial.

MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk soft-tissue sarcoma (STS) patients in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. Additionally, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by immunohistochemistry in tissue microarrays from STS patients and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured based on apoptosis. MRP-1 was evaluable in 231 out of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR=1.78 (95%CI, 1.11-2.83)], p=0.016, in the multivariate analysis, with a trend for a worse OS [HR=1.78 (95%CI, 0.97-3.25)], p=0.062. In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk STS patients treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0315

Front Cell Dev Biol. 2021 ;9 715126

Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy.

Ignacio Campillo-Marcos, Eva Monte-Serrano, Elena Navarro-Carrasco, Raúl García-González, Pedro A Lazo.

Background: Chromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs).
Methods: KMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis.
Results: Chaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation, and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death.
Conclusion: KMT inhibitors could function as sensitizers to DNA damage-based therapies and be used in novel synthetic lethality strategies for sarcoma treatment.

Keywords: 53BP1 foci; DNA repair; H2AX foci; chaetocin; doxorubicin; histone methylation; ionizing radiation; tazemetostat

DOI: https://doi.org/10.3389/fcell.2021.715126