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Background Anti‐PD1 checkpoint inhibitors (ICI) represent an established standard‐of‐care for patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥2; the benefit of ICI in this population is therefore unknown. Methods We retrospectively reviewed RMHNSCC patients who received 1+ dose of ICI at our institution between 2013 and 2019. Demographic and clinical data were obtained; the latter included objective response (ORR), toxicity, and any unplanned hospitalization (UH). Associations were explored using uni‐ and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, toxicity, and UH were evaluated with logistic regression. Results Of the 152 patients, 29 (19%) had an ECOG PS ≥2. Sixty‐six (44%) experienced toxicity; 54 (36%) had a UH. A multivariate model for OS containing PS, smoking status, and HPV status demonstrated a strong association between ECOG ≥2 and shorter OS (p < 0.001; HR = 3.30, CI = 2.01–5.41). An association between OS and former (vs. never) smoking was also seen (p < 0.001; HR = 2.17, CI = 1.41–3.35); current smoking did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06–0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05—5.71). There was no significant association between toxicity and any patient characteristic. Conclusions We observed inferior OS, ORR, and rates of UH among ICI‐treated RMHNSCC patients with ECOG 2/3. Our findings help frame discussion of therapeutic options in this poor‐risk population. Relative to those with a performance status of 0‐1, patients with an Eastern Cooperative Oncology Group performance status 2 who received immune checkpoint inhibitors for recurrent/metastatic head and neck cancer have poorer response rates and overall survival as well as increased rates of unplanned hospitalization; no significant difference in toxicity was seen.

Transcription cycle of RNA polymerase II (RNAPII) features three stages: initiation, elongation, and termination. Termination, closely linked with pre-mRNA 3’ processing, dissociates RNAPII from DNA and releases the nascent RNA transcript. Efficient termination is required for maintaining a pool of RNAPII that is available for re-entry into new transcription cycle. Previous results showed that inactivation of checkpoint kinase Mec1p in the absence of exogenous genotoxic stress downregulates the efficiency of transcription termination and reduces the efficiency of pre-mRNA cleavage at the polyadenylation (pA) sites. We report here that Mec1p impacts transcription termination at two distinct steps. Mec1p promotes recruitment of Pcf11p, a subunit of the cleavage factor IA (CF IA), to 3’ ends of genes, and regulates the activity of torpedo exonuclease Rat1p. Deletion of Mec1p or mutations that prevent activation of Mec1p partially suppress both transcription termination defects as well as rRNA and snoRNA processing defects in rat1-1 cells. These results suggest that Mec1p regulates features of Rat1p function that are shared by termination of RNAPII transcription and rRNA and snoRNA processing and imply that the kinase activity of Mec1p downregulates Rat1p function. Cumulatively, our results reveal a new role for checkpoint kinase Mec1p in transcription termination and regulation of the torpedo exonuclease Rat1p.

Galls induced by plant-parasitic nematodes involve a hyperactivation of the plant mitotic and endocycle machinery for their profit. Dedifferentiation of host root cells includes drastic cellular and molecular readjustments. In such background, potential DNA damage in the genome of gall cells is eminent. We questioned if DNA damage checkpoints activation followed by DNA repair occurred, or was eventually circumvented, in nematode-induced galls. Galls display transcriptional activation of the DNA damage checkpoint kinase WEE1, correlated with its protein localization in the nuclei. The promoter of the stress marker gene SMR7 was evaluated under the WEE1-knockout background. Drugs inducing DNA damage and a marker for DNA repair, PARP1 were used to understand mechanisms that might cope with DNA damage in galls. Our functional study revealed that gall cells lacking WEE1 conceivably entered mitosis prematurely disturbing the cell cycle despite the loss of genome integrity. The disrupted nuclei phenotype in giant cells hinted to the accumulation of mitotic defects. As well, WEE1-knockout in Arabidopsis and downregulation in tomato repressed infection and reproduction of root-knot nematodes. Together with data on DNA damaging drugs, we suggest a conserved function for WEE1 controlling a G1/S cell cycle arrest in response to replication defect in galls.

It has been more than three decades since the discovery of multifunctional factors, the Non-POU-Domain-Containing Octamer-Binding Protein, NonO, and the Splicing Factor Proline- and Glutamine-Rich, SFPQ. Some of their functions, including their participation in transcriptional and posttranscriptional regulation as well as their contribution to paraspeckle subnuclear body organization, have been well documented. In this review, we focus on several other established roles of NonO and SFPQ, including their participation in the cell cycle, nonhomologous end-joining (NHEJ), homologous recombination (HR), telomere stability, childhood birth defects and cancer. In each of these contexts, the absence or malfunction of either or both NonO and SFPQ leads to either genome instability, tumor development or mental impairment.

Artesunate (ART), an effective antimalarial semisynthetic derivative of artemisinin, exhibits antitumour properties, but the mechanism(s) involved remain elusive. In this study, we investigated the antitumour effects of ART on human oesophageal squamous cell carcinoma (ESCC) cell lines. Treatment of ESCC cell lines with ART resulted in the production of excessive reactive oxygen species (ROS) that induced DNA damage, reduced cell proliferation and inhibited clonogenicity via G1-S cell cycle arrest and/or apoptosis in vitro. The administration of ART to nude mice with ESCC cell xenografts inhibited tumour formation in vivo. However, the cytotoxicity of ART strongly differed among the ESCC cell lines tested. Transcriptomic profiling revealed that although the expression of large numbers of genes in ESCC cell lines was affected by ART treatment, these genes could be functionally clustered into pathways involved in regulating cell cycle progression, DNA metabolism and apoptosis. We revealed that p53 and Cdk4/6-p16-Rb cell cycle checkpoint controls were critical determinants required for mediating ART cytotoxicity in ESCC cell lines. Specifically, KYSE30 cells with p53 Mut /p16 Mut were the most sensitive to ART, KYSE150 and KYSE180 cells with p53 Mut /p16 Nor exhibited intermediate responses to ART, and Eca109 cells with p53 Nor /p16 Nor exhibited the most resistance to ATR. Consistently, perturbation of p53 expression using RNA interference (RNAi) and/or Cdk4/6 activity using the inhibitor palbociclib altered ART cytotoxicity in KYSE30 cells. Given that the p53 and Cdk4/6-cyclin D1-p16-Rb genes are commonly mutated in ESCC, our results potentially shed new light on neoadjuvant chemotherapy strategies for ESCC.

Introduction BI 891065, a second mitochondria‐derived activator of caspases mimetic targets the inhibitor of apoptosis (IAP) family member cIAP1. We describe two first‐in‐human phase 1 trials assessing BI 891065 ± the anti‐programmed cell death protein‐1 (PD1) antibody, ezabenlimab, in advanced solid tumors. Methods Trials were conducted in the USA (NCT03166631) and Japan (NCT04138823). Dose escalation of BI 891065 monotherapy (part A) and combined with ezabenlimab (part B) was guided by a Bayesian Logistic Regression Model with overdose control. Primary endpoints were maximum tolerated dose (MTD) and number of patients with dose‐limiting toxicities (DLTs) in Cycle 1. Other endpoints included objective response (RECIST v 1.1), pharmacokinetics, and changes in peripheral blood mononuclear cell (PBMC) and tumor cIAP1 levels. Results Twenty‐five patients (USA study) received 5–400 mg daily BI 891065 monotherapy; 12 patients (Japan study) received 100 mg daily, 200 mg daily, or 200 mg twice‐daily BI 891065 monotherapy. No DLTs occurred in the USA study; three occurred in the Japan study: grade 3 increased bilirubin (n = 2) and maculopapular rash (n = 1). Neither study reached MTD for monotherapy. Treatment‐related adverse events (TRAEs) occurred in 52% and 75% of patients, respectively. BI 891065 plus ezabenlimab combination (USA study part B only) was received by 37 patients (50–400 mg daily, 200 mg twice‐daily) plus ezabenlimab (240 mg fixed‐dose, Day 1 of 21‐day cycles). One DLT occurred (grade 2 pneumonitis). MTD was not reached. TRAEs occurred in 81% of patients. Neither study reported objective responses; 25%–40% and 35% of patients achieved stable disease with BI 891065 monotherapy and the combination, respectively. cIAP1 levels were reduced in PBMCs and biopsies. Conclusions BI 891065 was tolerable in patients with advanced solid tumors, demonstrating target engagement as monotherapy and combined with ezabenlimab. Both studies ended early due to efficacy data that were insufficiently promising to justify continuation. Trial Registration NCT03166631, NCT04138823

Covalent post-translational modification of proteins by ubiquitin and ubiquitin-like factors has emerged as a general mechanism to regulate myriad intra-cellular processes. The addition and removal of ubiquitin or ubiquitin-like proteins from factors has recently been demonstrated as a key mechanism to modulate DNA damage response (DDR) pathways. It is thus, timely to evaluate the potential for ubiquitin pathway enzymes as DDR drug targets for therapeutic intervention. The synthetic lethal approach provides exciting opportunities for the development of targeted therapies to treat cancer: most tumours have lost critical DDR pathways, and thus rely more heavily on the remaining pathways, while normal tissues are still equipped with all DDR pathways. Here, we review key deubiquitylating enzymes (DUBs) involved in DDR pathways, and describe how targeting DUBs may lead to selective therapies to treat cancer patients.

Early studies in lower Eukaryotes have defined a role for the members of the NimA related kinase (Nek) family of protein kinases in cell cycle control. Expansion of the Nek family throughout evolution has been accompanied by their broader involvement in checkpoint regulation and cilia biology. Moreover, mutations of Nek family members have been identified as drivers behind the development of ciliopathies and cancer. Recent advances in studying the physiological roles of Nek family members utilizing mouse genetics and RNAi-mediated knockdown are revealing intricate associations of Nek family members with fundamental biological processes. Here, we aim to provide a comprehensive account of our understanding of Nek kinase biology and their involvement in cell cycle, checkpoint control and cancer.

Introduction Avelumab + axitinib was approved in Japan in December 2019 for the treatment of curatively unresectable or metastatic renal cell carcinoma (RCC) based on results from the JAVELIN Renal 101 trial. Materials and Methods To evaluate the safety and effectiveness of avelumab + axitinib in older patients in general clinical practice in Japan, an ad hoc analysis of data from post‐marketing surveillance (PMS) by age group was conducted. Results The analysis population included 328 patients who had received ≥1 dose of avelumab and were enrolled between December 2019 and May 2021. In total, 100 patients (30.5%) were aged ≤64 years, 130 (39.6%) were aged 65–74 years, and 98 (29.9%) were aged ≥75 years. Within these age groups, adverse drug reactions (ADRs) of safety specifications of any grade occurred in 46 (46.0%), 71 (54.6%), and 56 (57.1%), and of grade ≥3 in 13 (13.0%), 23 (17.7%), and 20 (20.4%), respectively. The most common ADRs of safety specifications across all age groups were thyroid dysfunction, infusion reactions, and hepatic function disorders. Median overall survival (OS) was not reached in any age group; 12‐month OS rates in patients aged ≤64, 65–74, or ≥75 years were 83.8%, 86.2%, and 80.0%, and objective response rates were 31.0%, 43.8%, and 30.6%, respectively. Discussion Analyses of PMS data show the safety and effectiveness of avelumab + axitinib across all age groups of patients with RCC in general clinical practice in Japan. The favorable benefit–risk profile was generally consistent with that observed in previous clinical trials. We report analyses from post‐marketing surveillance of avelumab + axitinib treatment in patients with advanced renal cell carcinoma in Japan in age subgroups: ≤64 years (n = 100), 65–74 years (n = 130), and ≥75 years (n = 98). Overall, safety and effectiveness were similar across age subgroups, suggesting that age alone is not a relevant consideration for avelumab + axitinib treatment. The favorable benefit–risk profile was generally consistent with that observed in previous clinical studies, further supporting the use of avelumab + axitinib treatment in this disease setting.

OBJECTIVEAppropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1β (HNF-1β) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1β in regulation of the cell cycle in CCA. METHODSTo clarify the effects of HNF-1β on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1β had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1β (+) cells were arrested in G2 phase because of DNA damage. RESULTSHNF-1β (−) cells died because of a checkpoint mechanism. G2 arrest of HNF-1β (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1β (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage–induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. CONCLUSIONSThe chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.