New tools for old drugs: Functional genetic screens to optimize current chemotherapy

Abstract

Despite substantial advances in the treatment of various cancers, many patients still receive anti-cancer therapies that hardly eradicate tumor cells but inflict considerable side effects. To provide the best treatment regimen for an individual patient, a major goal in molecular oncology is to identify predictive markers for a personalized therapeutic strategy. Regarding novel targeted anti-cancer therapies, there are usually good markers available. Unfortunately, however, targeted therapies alone often result in rather short remissions and little cytotoxic effect on the cancer cells. Therefore, classical chemotherapy with frequent long remissions, cures, and a clear effect on cancer cell eradication remains a corner stone in current anti-cancer therapy. Reliable biomarkers which predict the response of tumors to classical chemotherapy are rare, in contrast to the situation for targeted therapy. For the bulk of cytotoxic therapeutic agents, including DNA-damaging drugs, drugs targeting microtubules or antimetabolites, there are still no reliable biomarkers used in the clinic to predict tumor response. To make progress in this direction, meticulous studies of classical chemotherapeutic drug action and resistance mechanisms are required. For this purpose, novel functional screening technologies have emerged as successful technologies to study chemotherapeutic drug response in a variety of models. They allow a systematic analysis of genetic contributions to a drug-responsive or −sensitive phenotype and facilitate a better understanding of the mode of action of these drugs. These functional genomic approaches are not only useful for the development of novel targeted anti-cancer drugs but may also guide the use of classical chemotherapeutic drugs by deciphering novel mechanisms influencing a tumor’s drug response. Moreover, due to the advances of 3D organoid cultures from patient tumors and in vivo screens in mice, these genetic screens can be applied using conditions that are more representative of the clinical setting. Patient-derived 3D organoid lines furthermore allow the characterization of the “essentialome”, the specific set of genes required for survival of these cells, of an individual tumor, which could be monitored over the course of treatment and help understanding how drug resistance evolves in clinical tumors. Thus, we expect that these functional screens will enable the discovery of novel cancer-specific vulnerabilities, and through clinical validation, move the field of predictive biomarkers forward. This review focuses on novel advanced techniques to decipher the interplay between genetic alterations and drug response.

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

“…Identifying the genetic dependencies of OSCC will, therefore, be critical for the development of novel therapies. Genome-scale functional genetic screens allow the high-throughput identification of genes that govern cell survival ( Gerhards and Rottenberg, 2018 ). Previously, such genes were identified using RNA interference (RNAi) technology ( McDonald et al, 2017 ; Tsherniak et al, 2017 ).…”

“…Previously, such genes were identified using RNA interference (RNAi) technology ( McDonald et al, 2017 ; Tsherniak et al, 2017 ). More recently, essential genes have been identified through the use of CRISPR-Cas9 technology due to its high specificity and efficiency compared to RNAi ( Gerhards and Rottenberg, 2018 ). Several studies using genome-wide CRISPR-Cas9 screen have already shown promising outcome in identifying novel cancer-specific vulnerabilities that are useful drug targets ( Steinhart et al, 2017 ; Wang et al, 2017 ), as well as improving the understanding of drug mechanism of action ( Barazas et al, 2018 ; Hou et al, 2017 ).…”

Co-delivery of dihydroartemisinin and docetaxel in pH-sensitive nanoparticles for treating metastatic breast cancerviathe NF-κB/MMP-2 signal pathway

“…The rst-line treatment of metastatic breast cancer is chemotherapy, but it is always associated with disadvantages such as systemic side effects and low efficiency, giving poor patient outcomes. 5,6 One of the most established technologies of drug delivery is the use of nanoscale delivery vehicles such as liposomes and nanoparticles for cancer therapy, which afford efficient accumulation of drugs at the tumor sites by exploiting the pathological characteristics of tumors like enhanced permeability and retention (EPR). 7 However, the therapeutic efficacy of some nanoscale delivery vehicles is suboptimal, mainly because of inefficient drug loading, short lifetime and inability to release drugs at specic sites.…”

From yeast to humans: Understanding the biology of DNA Damage Response (DDR) kinases

“…Recently, the advent of genome-editing tools in human cell lines, combined with new DDR kinase inhibitors, have been successfully applied for the screen of synthetic lethal interactions, offering new insights for cancer treatment (Ruiz et al, 2016;Gerhards and Rottenberg, 2018;Wang et al, 2019). The kinase ATR, for example, have come under the spotlight in recent years as prominent therapeutic target in cancer (Foote et al, 2015).…”