SLIDE-VIP: a comprehensive, cell line- and patient-based framework for synthetic lethality prediction in DNA damage repair, chromatin remodeling and cell cycle

Abstract

Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing cancer therapies. However, identification of SL interactions is challenging, due to a large number of possible gene pairs, inherent noise and confounding factors in the observed signal. To discover robust SL interactions, we devised SLIDE-VIP, a novel framework combining eight statistical tests, including a new patient data-based test iSurvLRT. SLIDE-VIP leverages multi-omics data from four different sources: gene inactivation cell line screens, cancer patient data, drug screens and gene pathways. We applied SLIDE-VIP to discover SL interactions between genes involved in DNA damage repair, chromatin remodeling and cell cycle, and their potentially druggable partners. The top 883 ranking SL candidates had strong evidence in cell line and patient data, 250-fold reducing the initial space of 200K pairs. Drug screen and pathway tests provided additional corroboration and insights into these interactions. We rediscovered well-known SL pairs such as RB1 and E2F3 or PRKDC and ATM, and in addition, proposed strong novel SL candidates such as PTEN and PIK3CB. In summary, SLIDE-VIP opens the door to the discovery of SL interactions with clinical potential. All analysis and visualizations are available via the online SLIDE-VIP WebApp.

Changing the Landscape of Solid Tumor Therapy From Apoptosis-Promoting to Apoptosis-Inhibiting Strategies

“…Huge efforts have been devoted to predict the biological outputs of the molecule(s) under study merely based on such perplexing signaling networks. As an example, Markowska et al [36] have recently presented a "firework" of overlapping signaling pathways that regulate chromatin remodeling, DNA damage response and cell cycle. The authors used a uniquely comprehensive workflow and identified several pairs of genes, related to these processes, that might display synthetic "lethal" interactions.…”

“…The authors used a uniquely comprehensive workflow and identified several pairs of genes, related to these processes, that might display synthetic "lethal" interactions. (This phenomenon refers to genetic interactions between two genes, where inactivation of each individual gene is compatible with a viable phenotype, whereas coinactivation of both genes is anticipated to result in lethality [36].) Figure 3.…”