Highlights d Radiogenetic profiling identifies ERCC6L2 as a major determinant of IR response d Loss of ERCC6L2 restores HR and causes PARPi resistance in BRCA1-deficient cells d ERCC6L2 contributes to NHEJ, possibly through its interaction with SFPQ d Patients with ERCC6L2-mutated UCEC show better survival upon RT
In recent years platinum (Pt) drugs have been found to be especially efficient to treat patients with cancers that lack a proper DNA damage response, e.g. due to dysfunctional BRCA1. Despite this knowledge, we are still missing helpful markers to predict Pt response in the clinic. We have previous-ly shown that volume-regulated anion channels, containing the subunits LRRC8A and LRRC8D, pro-mote the uptake of cisplatin and carboplatin in BRCA1-proficient cell lines. Here, we show that the loss of LRRC8A or LRRC8D significantly reduces the uptake of cis- and carboplatin in BRCA1;p53-deficient mouse mammary tumor cells. This results in reduced DNA damage and in vivo drug resistance. In contrast to Lrrc8a, the deletion of the Lrrc8d gene does not affect the viability and fertility of mice. Interestingly, Lrrc8d-/- mice tolerate a two-fold cisplatin maximum-tolerable dose. This allowed us to establish a mouse model for intensified Pt-based chemotherapy, and we found that an increased cis-platin dose eradicates BRCA1;p53-deficient tumors, whereas eradication is not possible in WT mice. Moreover, we show that decreased expression of LRRC8A/D in head and neck squamous cell carci-noma patients, who are treated with a Pt-based chemoradiotherapy, leads to decreased overall sur-vival of the patients. In particular, high cumulative cisplatin dose treatments lost their efficacy in pa-tients with a low LRRC8A/D expression in their cancers. Our data therefore suggest that LRRC8A and LRRC8D should be included in a prospective trial to predict the success of intensified cis- or car-boplatin-based chemotherapy.
MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to sites of damage to promote the recruitment of other factors, including the 53BP1-mediated DSB repair pathway. By studying mechanisms of poly(ADP-ribose) polymerase inhibitor (PARPi) resistance in BRCA2;p53-deficient mouse mammary tumors, we identified a thus far unknown role of MDC1 in replication fork biology. MDC1 localizes at active replication forks during normal fork replication and its loss reduces fork speed. We show that MDC1 contributes to the restart of replication forks and thereby promotes sensitivity to PARPi and cisplatin. Loss of MDC1 causes MRE11-mediated resection, resulting in delayed fork restart. This improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. Hence, our results show a role for MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.
A 12-year-old Haflinger gelding with a history of a persistent cough was referred for evaluation of a severe lameness of the left forelimb. An excision of the right nictitans had been performed 2 years prior to presentation, and a squamous cell carcinoma (SCC) with embolic neoplastic cells in several blood vessels had been confirmed by histopathology. The origin of the lameness could not be localised with regional analgesia; therefore, a nuclear scintigraphic examination was performed. This revealed an area of marked increased radiopharmaceutical uptake at the level of the caudodorsal border of the left scapula. Further examination, including ultrasound-guided biopsy of the suspect region, confirmed the presence of SCC invading the scapula. Due to poor a prognosis, the horse was subjected to euthanasia. Prior to euthanasia, the gelding was tested homozygous for the missense variant in the damage-specific DNA-binding protein 2 (DDB2) gene, which is reported as a risk factor for the development of nictitans SCC in Haflinger horses. Postmortem evaluation revealed multiple SCC metastasis, affecting the scapula, the liver and the lungs. To the authors' knowledge, this is the first reported case of bone metastasis following a primary periocular SCC in a horse.
<p>Analysis of publicly available ovarian cancer dataset to identify the association of LRRC8A or LRRC8D expression with outcome of chemotherapy with cisplatin</p>
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