REV1 Inhibition Enhances Radioresistance and Autophagy

SIMPLE SUMMARY: Cancer resistance to therapy continues to be the biggest challenge in treating patients. Targeting the mutagenic translesion synthesis (TLS) polymerase REV1 was previously shown to sensitize cancer cells to chemotherapy. In this study, we tested the ability of REV1 inhibitors to radiation therapy and observed a lack of radiosensitization. In addition, we observed REV1 inhibition to trigger an autophagy stress response. Because reduction of REV1 triggered autophagy and failed to radiosensitize cells, we hypothesize REV1 expression dynamics might link cancer cell response to radiation treatment through the potential induction of autophagy. ABSTRACT: Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens

Mutational heterogeneity in cancer and the search for new cancer genes

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention

Global Position Statement: Stigma, Mental Illness and Diversity

Careif is an international mental health charity that works towards protecting and promoting mental health, wellbeing, resilience and resourcefulness with a special focus towards eliminating inequalities and strengthening social justice. Our principles include working creatively with humility, dignity and balanced partnerships in order to ensure that all cultures and societies play their part in our mission of protecting and promoting mental health and wellbeing. We do this by respecting the traditions of all world societies, whilst believing that culture and traditions can evolve for even greater benefit to individuals and society. Globalisation has created culturally rich and diverse societies. During the past several decades, there has been a steadily increasing recognition of the importance of societal and cultural influences on life and health. Societies are becoming multi-ethnic and poly-cultural in nature worldwide, where different groups enrich each other's lives with their unique culture/s. Cultural transition and acculturation is often discussed as relevant to migrants and mentions the need to integrate, when in fact it is of relevance to all cultures in an ever interconnecting world. It is indeed necessary to be equipped with knowledge about cultures and their influence on mental health and illness. Culturally informed mental health care is rapidly moving from an attitudinal orientation to an evidence-based approach, therefore understanding culture and mental health care becomes greater than a health care issue

The role of REV1 in cancer resistance to radiation therapy

Despite the availability of several treatment modalities, cancer resistance is a prominent clinical challenge. Cancer recurrence is often observed in patients after initial treatment leading to acquired resistance. Amongst the different biological pathways responsible for treatment resistance, translesion synthesis (TLS), a DNA damage tolerance mechanism has recently been implicated in causing cancer resistance to chemotherapy (Yamanaka et al., 2017). The REV1 TLS protein plays a major role in this pathway, where it functions as a key scaffolding protein that helps facilitate DNA damage bypass. Recently, targeting REV1 with small molecule inhibitors was shown to sensitize cancer cells to chemotherapeutic drugs (Wojtaszek et al., 2019). However, it is not known whether REV1 inhibition would similarly sensitize cancer cells to radiation therapy, another common treatment module in cancer patients. We proposed that REV1 is a potential target for sensitizing cancer cells to radiation treatment. We performed cytotoxicity and colony survival assays upon treating cancer cells with REV1 inhibitors and ionizing radiations to determine whether REV1 inhibition similarly sensitizes cancer cells to ionizing radiation (IR) treatment. Remarkably, we found that REV1 inhibition fails to sensitize cells to radiotherapy. Instead, REV1 inhibition induces autophagy which might be enhancing radioresistance. Immunofluorescence assays were used in the detection of autophagy. Ascertaining the mechanisms of REV1-inhibition dependent cancer resistance is a key component in addressing the clinical challenge of cancer therapy resistance

Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium

Summary: The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31–36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%–50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike

Mutational heterogeneity in cancer and the search for new cancer-associated genes

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer