Nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARγ.

Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic strategy against cancer. One transmembrane component of the NPC is POM121, encoded by a tandem gene locus POM121A/C on chromosome 7. Overexpression of POM121 is associated with metabolic diseases (e.g., diabetes) and unfavorable clinical outcome in patients with colorectal cancer (CRC). Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor with anti-diabetic and anti-tumoral efficacy. It is inhibited by export from the nucleus to the cytosol via the RAS-RAF-MEK1/2-ERK1/2 signaling pathway, a major oncogenic driver of CRC. We therefore hypothesized that POM121 participates in the transport of PPARγ across the NPC to regulate its transcriptional activity on genes involved in metabolic and tumor control. We found that POM121A/C mRNA was enriched and POM121 protein co-expressed with PPARγ in tissues from CRC patients conferring poor prognosis. Its interactome was predicted to include proteins responsible for tumor metabolism and immunity, and in-silico modeling provided insights into potential 3D structures of POM121. A peptide region downstream of the nuclear localization sequence (NLS) of POM121 was identified as a cytoplasmic interactor of PPARγ. POM121 positivity correlated with the cytoplasmic localization of PPARγ in patients with KRAS mutant CRC. In contrast, POM121A/C silencing by CRISPR/Cas9 sgRNA or siRNA enforced nuclear accumulation of PPARγ and activated PPARγ target genes promoting lipid metabolism and cell cycle arrest resulting in reduced proliferation of human CRC cells. Our data suggest the POM121-PPARγ axis as a potential drugable target in CRC.

Onset Time and Characteristics of Postprocedural Bleeding after Endoscopic Resection of Colorectal Lesions: A Multicenter Retrospective Study.

INTRODUCTION: Postprocedural bleeding is a major adverse event after endoscopic resection of colorectal lesions, but the optimal surveillance time after endoscopy is unclear. In this study, we determined onset time and characteristics of postprocedural bleeding events. METHODS: We retrospectively screened patients who underwent endoscopic resection of colorectal lesions at three German hospitals between 2010 and 2019 for postprocedural bleeding events using billing codes. Only patients who required re-endoscopy were included for analysis. For identified patients, we collected demographic data, clinical courses, characteristics of colorectal lesions, and procedure-related variables. Factors associated with late-onset bleeding were determined by univariate and multivariate logistic regression analysis. RESULTS: From a total of 6,820 patients with eligible billing codes, we identified 113 cases with postprocedural bleeding after endoscopic mucosal (61.9%) or snare resection (38.1%) that required re-endoscopy. The median size of the culprit lesion was 20 mm (interquartile range 14-30 mm). The median onset time of postprocedural bleeding was day 3 (interquartile range: 1-6.5 days), with 48.7% of events occurring within 48 h. Multivariate logistic regression analysis demonstrates that a continued intake of antiplatelet drugs (OR: 3.98, 95% CI: 0.89-10.12, p = 0.025) and a flat morphology of the colorectal lesion (OR: 2.98, 95% CI: 1.08-8.01, p = 0.031) were associated with an increased risk for late postprocedural bleeding (>48 h), whereas intraprocedural bleeding was associated with a decreased risk (OR: 0.12, 95% CI: 0.04-0.50, p = 0.001). CONCLUSION: Significant postprocedural bleeding can occur up to 18 days after endoscopic resection of colorectal lesions, but was predominantly observed within 48 h. Continued intake of antiplatelet drugs and a flat polyp morphology are associated with risk for late postprocedural bleeding.

Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial.

PURPOSE: This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a perioperative treatment for patients with resectable esophagogastric adenocarcinoma (EGA). METHODS: DANTE started as multicenter, randomized phase II trial, which was subsequently converted to a phase III trial. Here, we present the results of the phase II proportion, focusing on surgical pathology and safety outcomes on an exploratory basis. Patients with resectable EGA (≥cT2 or cN+) were assigned to either four preoperative and postoperative cycles of FLOT combined with ATZ, followed by eight cycles of ATZ maintenance (arm A) or FLOT alone (arm B). RESULTS: Two hundred ninety-five patients were randomly assigned (A, 146; B, 149) with balanced baseline characteristics between arms. Twenty-three patients (8%) had tumors with microsatellite instability (MSI), and 58% patients had tumors with a PD-L1 combined positive score (CPS) of ≥1. Surgical morbidity (A, 45%; B, 42%) and 60-day mortality (A, 3%; B, 2%) were comparable between arms. Downstaging favored arm A versus arm B (ypT0, 23% v 15% [one-sided P = .044]; ypT0-T2, 61% v 48% [one-sided P = .015]; ypN0, 68% v 54% [one-sided P = .012]). Histopathologic complete regression rates (pathologic complete response or TRG1a) were higher after FLOT plus ATZ (A, 24%; B, 15%; one-sided P = .032), and the difference was more pronounced in the PD-L1 CPS ≥10 (A, 33%; B, 12%) and MSI (A, 63%; B, 27%) subpopulations. Complete margin-free (R0) resection rates were relatively high in both arms (A, 96%; B, 95%). The incidence and severity of adverse events were similar in both groups. CONCLUSION: Within the limitations of the exploratory nature of the data, the addition of ATZ to perioperative FLOT is safe and improved postoperative stage and histopathologic regression.

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

The Roles of Secreted Wnt Ligands in Cancer.

Wnt ligands are secreted signaling proteins that display a wide range of biological effects. They play key roles in stimulating Wnt signaling pathways to facilitate processes such as tissue homeostasis and regeneration. Dysregulation of Wnt signaling is a hallmark of many cancers and genetic alterations in various Wnt signaling components, which result in ligand-independent or ligand-dependent hyperactivation of the pathway that have been identified. Recently, research is focusing on the impact of Wnt signaling on the interaction between tumor cells and their micro-environment. This Wnt-mediated crosstalk can act either in a tumor promoting or suppressing fashion. In this review, we comprehensively outline the function of Wnt ligands in different tumor entities and their impact on key phenotypes, including cancer stemness, drug resistance, metastasis, and immune evasion. Lastly, we elaborate approaches to target Wnt ligands in cancer therapy.

Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer.

Radiotherapy is an important component of current treatment options for colorectal cancer (CRC). It is either applied as neoadjuvant radiotherapy to improve local disease control in rectal cancers or for the treatment of localized metastatic lesions of CRC. DNA double-strand breaks (DSBs) are the major critical lesions contributing to ionizing radiation (IR)-induced cell death. However, CRC stem cells promote radioresistance and tumor cell survival through activating cell-cycle checkpoints to trigger the DNA damage response (DDR) and DNA repair after exposure to IR. A promising strategy to overcome radioresistance is to target the DDR and DNA repair pathways with drugs that inhibit activated cell-cycle checkpoint proteins, thereby improving the sensitivity of CRC cells to radiotherapy. In this review, we focus on the preclinical studies and advances in clinical trials of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1 and poly (ADP-ribose) polymerase 1 (PARP1) kinase inhibitors in CRC. Importantly, we also discuss the selective radiosensitization of CRC cells provided by synthetic lethality of these inhibitors and the potential for widening the therapeutic window by targeting the DDR and DNA repair pathways in combination with radiotherapy and immunotherapy.

Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial.

BACKGROUND: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population. METHODS: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244. FINDINGS: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment. INTERPRETATION: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment. FUNDING: Bristol Myers Squibb.

The drug-induced phenotypic landscape of colorectal cancer organoids.

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them.

Sequential Geriatric Assessment in Older Patients with Colorectal Cancer during Chemotherapy: Subgroup Analysis of a Prospective, Multicenter Study EpiReal 75.

INTRODUCTION: Colorectal cancer (CRC) is a disease of older patients, but evidence-based guidelines for chemotherapy in older patients are scarce. Geriatric assessment (GA) evaluates a patient's functional status (FS) and helps in decision-making when choosing chemotherapy for older patients. However, the change of FS during chemotherapy is rarely studied as GA is mostly performed once instead of sequentially. METHODS: We performed a subgroup analysis of a prospective, multicenter study EpiReal 75. Patients aged ≥75 years with gastrointestinal malignancy prior to initiation of chemotherapy or receiving palliative chemotherapy were screened. We defined geriatric core assessments including the Eastern Cooperative Oncology Group score, Barthel's activities of daily living (ADL) scale, Lawton's instrumental activities of daily living (IADL) scale, and G-8 questionnaire, which were performed at baseline and repeated every 3 months. Quality of life (QoL) assessed by QLQ-C30 questionnaire was also re-evaluated every 3 months. We defined any deterioration in any of the geriatric parameters as unstable in the corresponding function. RESULTS: 28 patients with CRC were enrolled between April 2014 and December 2018. 20 patients were evaluable for statistical analysis with a mean age of 78.5 years (range, 75-88). Most patients received chemotherapy in palliative setting. During 3 months of chemotherapy, 25% of patients became more dependent as measured by ADL or IADL. During a median follow-up of 15 months, patients with unstable ADL or IADL had a significantly shorter overall survival (OS) than those with stable ADL or IADL (plogrank = 0.0055 and 0.0253, respectively), without a significant difference in progression-free survival (PFS). Also, unstable IADL correlated with a deterioration in aspects of QoL such as role functioning and emotional functioning (p = 0.0189 and 0.0239, respectively). 20% of patients experienced treatment-related grade 3 adverse events (AEs), no grade 4-5 AEs occurred. CONCLUSION: Sequential GA revealed changes in FS in older patients with CRC receiving chemotherapy. A deterioration of FS during chemotherapy did not influence PFS but had a negative impact on OS and QoL. It is therefore important to maintain FS in older patients with cancer, and regular performance of geriatric core assessments should be encouraged in the clinical practice.

Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors.

Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents is a promising treatment strategy for advanced cancers. Here, we exploited the concept of synthetic lethality to identify epigenetic targets that act synergistically with histone deacetylase (HDAC) inhibitors to reduce the growth of CRC. We applied a pooled CRISPR-Cas9 screen using a custom sgRNA library directed against 614 epigenetic regulators and discovered that knockout of the euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1/2) strongly enhanced the antiproliferative effect of clinically used HDAC inhibitors. Using tissue microarrays from 1066 CRC samples with different tumor stages, we showed that low EHMT2 protein expression is predominantly found in advanced CRC and associated with poor clinical outcome. Cotargeting of HDAC and EHMT1/2 with specific small molecule inhibitors synergistically reduced proliferation of CRC cell lines. Mechanistically, we used a high-throughput Western blot assay to demonstrate that both inhibitors elicited distinct cellular mechanisms to reduce tumor growth, including cell cycle arrest and modulation of autophagy. On the epigenetic level, the compounds increased H3K9 acetylation and reduced H3K9 dimethylation. Finally, we used a panel of patient-derived CRC organoids to show that HDAC and EHMT1/2 inhibition synergistically reduced tumor viability in advanced models of CRC.

Cross-Talk between p53 and Wnt Signaling in Cancer.

Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are critically involved in cancer onset and progression. Over recent decades, a high level of interaction between the two pathways has been revealed. Here, we provide a comprehensive overview of molecular interactions between the p53 and Wnt pathway discovered in cancer, including complex feedback loops and reciprocal transactivation. The mutational landscape of genes associated with p53 and Wnt signaling is described, including mutual exclusive and co-occurring genetic alterations. Finally, we summarize the functional consequences of this cross-talk for cancer phenotypes, such as invasiveness, metastasis or drug resistance, and discuss potential strategies to pharmacologically target the p53-Wnt interaction.

Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models.

Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer.

Personalized functional profiling using ex-vivo patient-derived spheroids points out the potential of an antiangiogenic treatment in a patient with a metastatic lung atypical carcinoid.

Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient's liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.

Neglected geriatric assessment and overtreatment of older patients with pancreatic cancer - Results from a prospective phase IV clinical trial.

BACKGROUND: Older patients with metastatic pancreatic cancer may suffer increased toxicity from intensive chemotherapy. Treatment individualization by geriatric assessment (GA) might improve functional outcome. METHODS: We performed a multicenter, phase IV, open label trial in patients ≥70 years with metastatic pancreatic adenocarcinoma. Patients underwent GA and were assigned to one of three categories based on their scores: Go-Go, Slow-Go, or Frail. These categories were intended to guide physician's treatment decisions when choosing to treat patients with nab-paclitaxel/gemcitabine (arm A), gemcitabine (arm B), or best supportive care (arm C). Primary objective was a stable (loss of five points or less) Barthel's Activities of Daily Living (ADL) score during chemotherapy; secondary endpoints included GA scores during therapy, safety, quality of life, response and survival rates. RESULTS: Thirty-two patients were enrolled in the trial in six centers in Germany (out of 135 planned), resulting in termination due to low recruitment. Fifteen patients were allocated to nab-paclitaxel/gemcitabine, fifteen to gemcitabine, and two to best supportive care by their physicians, although according to their GA scores 29 patients (91%) were categorized as Slow-Go and three (9%) as Go-Go. Thus, fifteen of 32 (47%) patients were misclassified and given a course of treatment inconsistent with their GA scores. Median progression-free survival (PFS) were 3.3 months and 9.1 months and median time to quality-of-life deterioration 13 days and 29 days in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Serious adverse events were reported in 11 (78.6%) patients in the nab-paclitaxel/gemcitabine and 8 (53.3%) patients in the gemcitabine arm. CONCLUSIONS: Clinical evaluations by investigators differed markedly from geriatric assessments, leading to potential overtreatment. In our modest sample size study, those patients undergoing more intensive therapy had a less favorable course.

Pancreatic Acinar Cell Carcinoma with Germline BRCA2 Mutation and Severe Pancreatic Panniculitis: A Case Report.

Pancreatic acinar cell carcinoma (ACC) is a rare malignant disease that displays distinct differences to pancreatic ductal adenocarcinoma. Here, we report the case of a patient with ACC and underlying breast cancer susceptibility gene 2 (BRCA2) germline mutation that developed severe pancreatic panniculitis (PP) during the course of the disease. The patient received a multimodal therapy including surgery, systemic chemotherapy, and targeted therapy with the PARP inhibitor olaparib, resulting in an overall survival of 47 months. Findings from this case are compared to the current knowledge on management of ACC and paraneoplastic PP.

[Prevention of gastrointestinal cancer]. / Prävention gastrointestinaler Tumore.

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following.

PPARγ induces PD-L1 expression in MSS+ colorectal cancer cells.

Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor "programmed-cell-death-1" (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment. Peroxisome proliferator-activated-receptor-gamma (PPARγ), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPARγ induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage. We found that PPARγ-agonists upregulate PD-L1 mRNA/protein expression in human gastrointestinal cancer cell lines and MSS+ patient-derived tumor organoids (PDOs). Mechanistically, PPARγ bound to and activated DNA-motifs similar to cognate PPARγ-responsive-elements (PPREs) in the proximal -2 kb promoter of the human PD-L1 gene. PPARγ-agonist reduced proliferation and viability of tumor cells in co-cultures with PD-L1 blocking Ab and lymphokine-activated killer cells (LAK) derived from the peripheral blood of CRC patients or healthy donors. Thus, metabolic modifiers improved the antitumoral response of immune checkpoint Ab, proposing novel therapeutic strategies for CRC.

Prognostic Cancer Gene Expression Signatures: Current Status and Challenges.

Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now able to explore molecular characteristics of tumors in detail and determine their clinical relevance. This has led to numerous prognostic and predictive gene expression signatures that have the potential to establish a classification of tumor subgroups by biological determinants. However, only a few gene signatures have reached the stage of clinical implementation so far. In this review article, we summarize the current status, and present and future challenges of prognostic gene signatures in three relevant cancer entities: breast cancer, colorectal cancer, and hepatocellular carcinoma.

Multi-omics integration identifies a selective vulnerability of colorectal cancer subtypes to YM155.

Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 157 CRC cell lines to CMS. By integrating results from large-scale drug screens, we discovered that the CMS1 subtype is highly vulnerable to the BIRC5 suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrated a 100-fold higher sensitivity of CMS1. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 CRC, low concentrations of YM155 induced apoptosis and expression signatures associated with ER stress-mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we further discovered a novel role of genes involved in LDL-receptor trafficking as modulators of YM155 sensitivity in the CRC cell line HCT116. Our work shows that combining drug response data with CMS classification in cell lines can reveal selective vulnerabilities and proposes YM155 as a novel subtype-specific drug.