Pharmacogenetic and pharmacogenomic discovery strategies

Genetic/genomic profiling at a single-patient level is expected to provide critical information for determining inter-individual drug toxicity and potential efficacy in cancer therapy. A better definition of cancer subtypes at a molecular level, may correspondingly complement such pharmacogenetic and pharmacogenomic approaches, for more effective personalized treatments. Current pharmacogenetic/pharmacogenomic strategies are largely based on the identification of known polymorphisms, thus limiting the discovery of novel or rarer genetic variants. Recent improvements in cost and throughput of next generation sequencing (NGS) are now making whole-genome profiling a plausible alternative for clinical procedures. Beyond classical pharmacogenetic/pharmacogenomic traits for drug metabolism, NGS screening programs of cancer genomes may lead to the identification of novel cancer-driving mutations. These may not only constitute novel therapeutic targets, but also effector determinants for metabolic pathways linked to drug metabolism. An additional advantage is that cancer NGS profiling is now leading to discovering targetable mutations, e.g., in glioblastomas and pancreatic cancers, which were originally discovered in other tumor types, thus allowing for effective repurposing of active drugs already on the market

NMR ‐identification of the interaction between BRCA1 and the intrinsically disordered monomer of the Myc‐associated factor X

International audienceAbstract The breast cancer susceptibility 1 (BRCA1) protein plays a pivotal role in modulating the transcriptional activity of the vital intrinsically disordered transcription factor MYC. In this regard, mutations of BRCA1 and interruption of its regulatory activity are related to hereditary breast and ovarian cancer (HBOC). Interestingly, so far, MYC's main dimerization partner MAX (MYC‐associated factor X) has not been found to bind BRCA1 despite a high sequence similarity between both oncoproteins. Herein, we show that a potential reason for this discrepancy is the heterogeneous conformational space of MAX, which encloses a well‐documented folded coiled‐coil homodimer as well as a less common intrinsically disordered monomer state—contrary to MYC, which exists mostly as intrinsically disordered protein in the absence of any binding partner. We show that when the intrinsically disordered state of MAX is artificially overpopulated, the binding of MAX to BRCA1 can readily be observed. We characterize this interaction by nuclear magnetic resonance (NMR) spectroscopy chemical shift and relaxation measurements, complemented with ITC and SAXS data. Our results suggest that BRCA1 directly binds the MAX monomer to form a disordered complex. Though probed herein under biomimetic in‐vitro conditions, this finding can potentially stimulate new perspectives on the regulatory network around BRCA1 and its involvement in MYC:MAX regulation