CRISPR Screens in Synthetic Lethality and Combinatorial Therapies for Cancer

SIMPLE SUMMARY: The synthetic lethality (SL) clinical success of PARP inhibitors in homologous recombinant deficient tumors has established a new concept for cancer treatment. For decades, efforts have centered on identifying genetic interactions for determining essential tumoral genes, and more recently, SL interactions to determine combinational treatments against persistent cancer reappearance. Currently, the feasibility of CRISPR screen methodology has emerged as the state of the art for uncovering new SL or viable interactors in the biology and treatment of cancers. We present the up-to-date research of numerous laboratories that take advantage of the genome-wide forward genetic CRISPR screen tools and protocols to identify cancer biomarkers, genetic interactions and novel therapies. Indeed, investigations are nowadays focused on defining innovative combinatorial treatments based on SL interactions. By coupling different drugs, concentration treatments can be lowered and therefore toxicity reduced. CRISPR screen technologies have deeply impacted cancer research to promote a robust advance in combined therapies. ABSTRACT: Cancer is a complex disease resulting from the accumulation of genetic dysfunctions. Tumor heterogeneity causes the molecular variety that divergently controls responses to chemotherapy, leading to the recurrent problem of cancer reappearance. For many decades, efforts have focused on identifying essential tumoral genes and cancer driver mutations. More recently, prompted by the clinical success of the synthetic lethality (SL)-based therapy of the PARP inhibitors in homologous recombinant deficient tumors, scientists have centered their novel research on SL interactions (SLI). The state of the art to find new genetic interactions are currently large-scale forward genetic CRISPR screens. CRISPR technology has rapidly evolved to be a common tool in the vast majority of laboratories, as tools to implement CRISPR screen protocols are available to all researchers. Taking advantage of SLI, combinatorial therapies have become the ultimate model to treat cancer with lower toxicity, and therefore better efficiency. This review explores the CRISPR screen methodology, integrates the up-to-date published findings on CRISPR screens in the cancer field and proposes future directions to uncover cancer regulation and individual responses to chemotherapy.