Prediction of immunotherapy response using mutations to cancer protein assemblies.

While immune checkpoint inhibitors have revolutionized cancer therapy, many patients exhibit poor outcomes. Here, we show immunotherapy responses in bladder and non-small cell lung cancers are effectively predicted by factoring tumor mutation burden (TMB) into burdens on specific protein assemblies. This approach identifies 13 protein assemblies for which the assembly-level mutation burden (AMB) predicts treatment outcomes, which can be combined to powerfully separate responders from nonresponders in multiple cohorts (e.g., 76% versus 37% bladder cancer 1-year survival). These results are corroborated by (i) engineered disruptions in the predictive assemblies, which modulate immunotherapy response in mice, and (ii) histochemistry showing that predicted responders have elevated inflammation. The 13 assemblies have diverse roles in DNA damage checkpoints, oxidative stress, or Janus kinase/signal transducers and activators of transcription signaling and include unexpected genes (e.g., PIK3CG and FOXP1) for which mutation affects treatment response. This study provides a roadmap for using tumor cell biology to factor mutational effects on immune response.

A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR-Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor's genetic profile modulates CDK4/6i resistance.

Cancer Mutations Converge on a Collection of Protein Assemblies to Predict Resistance to Replication Stress.

Rapid proliferation is a hallmark of cancer associated with sensitivity to therapeutics that cause DNA replication stress (RS). Many tumors exhibit drug resistance, however, via molecular pathways that are incompletely understood. Here, we develop an ensemble of predictive models that elucidate how cancer mutations impact the response to common RS-inducing (RSi) agents. The models implement recent advances in deep learning to facilitate multidrug prediction and mechanistic interpretation. Initial studies in tumor cells identify 41 molecular assemblies that integrate alterations in hundreds of genes for accurate drug response prediction. These cover roles in transcription, repair, cell-cycle checkpoints, and growth signaling, of which 30 are shown by loss-of-function genetic screens to regulate drug sensitivity or replication restart. The model translates to cisplatin-treated cervical cancer patients, highlighting an RTK-JAK-STAT assembly governing resistance. This study defines a compendium of mechanisms by which mutations affect therapeutic responses, with implications for precision medicine. SIGNIFICANCE: Zhao and colleagues use recent advances in machine learning to study the effects of tumor mutations on the response to common therapeutics that cause RS. The resulting predictive models integrate numerous genetic alterations distributed across a constellation of molecular assemblies, facilitating a quantitative and interpretable assessment of drug response. This article is featured in Selected Articles from This Issue, p. 384.

Multiscale community detection in Cytoscape.

Detection of community structure has become a fundamental step in the analysis of biological networks with application to protein function annotation, disease gene prediction, and drug discovery. This recent impact creates a need to make these techniques and their accompanying visualization schemes available to a broad range of biologists. Here we present a service-oriented, end-to-end software framework, CDAPS (Community Detection APplication and Service), that integrates the identification, annotation, visualization, and interrogation of multiscale network communities, accessible within the popular Cytoscape network analysis platform. With novel design principles, CDAPS addresses unmet new challenges, such as identifying hierarchical community structures, comparison of outputs generated from diverse network resources, and easy deployment of new algorithms, to facilitate community-sourced science. We demonstrate that the CDAPS framework can be applied to high-throughput protein-protein interaction networks to gain novel insights, such as the identification of putative new members of known protein complexes.

Analysis of the structural variability of topologically associated domains as revealed by Hi-C.

Three-dimensional chromosome structure plays an integral role in gene expression and regulation, replication timing, and other cellular processes. Topologically associated domains (TADs), building blocks of chromosome structure, are genomic regions with higher contact frequencies within the region than outside the region. A central question is the degree to which TADs are conserved or vary between conditions. We analyze 137 Hi-C samples from 9 studies under 3 measures to quantify the effects of various sources of biological and experimental variation. We observe significant variation in TAD sets between both non-replicate and replicate samples, and provide initial evidence that this variability does not come from genetic sequence differences. The effects of experimental protocol differences are also measured, demonstrating that samples can have protocol-specific structural changes, but that TADs are generally robust to lab-specific differences. This study represents a systematic quantification of key factors influencing comparisons of chromosome structure, suggesting significant variability and the potential for cell-type-specific structural features, which has previously not been systematically explored. The lack of observed influence of heredity and genetic differences on chromosome structure suggests that factors other than the genetic sequence are driving this structure, which plays an important role in human disease and cellular functioning.