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Ruthenium (Ru) and osmium (Os) complexes are of sustained interest in cancer research and may be alternative to platinum-based therapy. We detail here three new series of ruthenium and osmium complexes, supported by physico-chemical characterizations, including time-dependent density functional theory, a combined experimental and computational study on the aquation reactions and the nature of the metal-arene bond. Cytotoxic profiles were then evaluated on several cancer cell lines although with limited success. Further investigations were, however, performed on the most active series using a genetic approach based on RNA interference and highlighted a potential multi-target mechanism of action through topoisomerase II, mitotic spindle, HDAC and DNMT inhibition., info:eu-repo/semantics/published

Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.

Summary Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Mutual exclusivity has been an empirically useful signal for identifying activating mutations that respond to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. We apply this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALKATI that was suggested to predict sensitivity to ALK inhibitors and we find that it is not mutually exclusive with key melanoma oncogenes. Furthermore, we find that ALKATI is not likely to be sufficient for cellular transformation or growth, and it does not predict single agent therapeutic dependency. Our work strongly disfavors the role of ALKATI as a targetable oncogenic driver that might be sensitive to single agent ALK treatment., Graphical abstract, Highlights • A method to test rare genomic findings for their relative conditional selection • ALKATI is not as mutually exclusive with BRAF or NRAS as they are with each other • ALKATI is not likely to be sufficient for cellular transformation or growth in vitro • Expressing activated oncogenic ALK in BRAFV600E melanoma cells is cytotoxic, Biological sciences; Systems biology; Cancer systems biology

Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Conditional selection, which includes mutual exclusivity, is a signal that has been empirically useful for identifying mutations that may be sensitive to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants and prevent robust conclusions from genomic data. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. This effectively creates positive control guideposts of mutual exclusivity in known driver genes that normalizes differences in mutation abundance. We applied this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALKATI, which has been the subject of a recent controversy in the literature. We reproduced some of the original cell transformation experiments, performed rescue experiments, and analyzed drug response data to revisit the original ALKATI findings. We found that ALKATI is not as mutually exclusive with BRAF or NRAS as BRAF and NRAS genes are with each other. We performed in vitro transformation assays and rescue assays that suggested that alternative transcript initiation in ALK is not likely to be sufficient for cellular transformation or growth and it does not predict single agent therapeutic dependency. Our work strongly disfavors the role of ALKATI as a targetable oncogenic driver that might be sensitive to single agent ALK treatment. The progress of other experimental agents in late-stage melanoma and our experimental and computational re-analysis led us to conclude that further single agent testing of ALK inhibitors in patients with ALKATI should be limited to cases where no other treatment hypotheses can be identified.

SummaryTheoretical treatments of evolutionary dynamics tend to model the probability that a single “resistant” species will arise in a population. However, experimental studies have identified a diversity of mutations that can lead to genetic resistance. By quantitatively predicting mutations that occur across an entire drug target during treatment, we identify and bridge a fundamental gap in drug resistance theory: that nucleotide/codon substitution biases can dictate which resistant variants arise in the clinic. We find that the likeliest mutation can beat the most resistant mutation. This creates a new paradigm in drug resistance that we term“survival of the likeliest”. We use epidemiological evidence in leukemia, isogenic experiments, stochastic dynamics, and large-scale simulations to support this theory. In addition, this work has strong implications for drug design because not all resistance liabilities are created equal. In pathogenic populations that exhibit survival of the likeliest, exploiting the least likely evolutionary path can minimize resistance across a population during widespread drug use, even when a vulnerability-free molecule or combination cannot be made.Data and Code Availabilityhttps://github.com/pritchardlabatpsu/SurvivalOfTheLikeliest/

SUMMARY Rationally designing drugs that last longer in the face of biological evolution is a critical objective of drug discovery. However, this goal is thwarted by the diversity and stochasticity of evolutionary trajectories that drive uncertainty in the clinic. Although biophysical models can qualitatively predict whether a mutation causes resistance, they cannot quantitatively predict the relative abundance of resistance mutations in patient populations. We present stochastic, first-principle models that are parameterized on a large in vitro dataset and that accurately predict the epidemiological abundance of resistance mutations across multiple leukemia clinical trials. The ability to forecast resistance variants requires an understanding of their underlying mutation biases. Beyond leukemia, a meta-analysis across prostate cancer, breast cancer, and gastrointestinal stromal tumors suggests that resistance evolution in the adjuvant setting is influenced by mutational bias. Our analysis establishes a principle for rational drug design: when evolution favors the most probable mutant, so should drug design., Graphical Abstract, In Brief Drug resistance is often addressed through next-generation drug design, but evolutionary diversity complicates these efforts. Here, Leighow et al. demonstrate that multi-scale models can quantitatively predict mutant frequency. We find that when heterogeneity is limited, analysis requires an understanding of substitution likelihood. We show that these models can inform evolutionarily optimized drug design.