Changes in ABC Transporter Expression during Hematopoiesis Cause Lineage-Biased Cytopenias in Patients Treated with Aurora Kinase Inhibitors

Chemotherapy-induced cytopenias are a prevalent and significant issue that worsens clinical outcomes and hinders the effective treatment of cancer. While they are classically associated with traditional cytotoxic chemotherapies, they also occur with newer targeted small molecule drugs and the factors that determine the hematotoxicity profiles of chemotherapies are not fully understood. Here, we explore why Aurora kinase inhibitor drugs cause preferential neutropenia when compared to the cytopenic profiles of targeted small molecule cancer drugs that are FDA approved. By studying drug responses of healthy human hematopoietic cells in vitro and analyzing existing published clinical datasets, we provide evidence that the enhanced vulnerability of neutrophil-lineage cells to Aurora kinase inhibitors is acquired at an early stage of differentiation and is caused by developmental changes in the expression pattern of ATP-binding cassette (ABC) transporters. These data show that hematopoietic cell-intrinsic expression of ABC transporters may be an important factor that determines how some chemotherapies affect the bone marrow. Disclosures David: AstraZeneca: Current Employment. Randle: AstraZeneca: Current Employment. Polanska: AstraZeneca: Current Employment. Urosevic: AstraZeneca: Current Employment. Travers: AstraZeneca: Ended employment in the past 24 months. Ingber: Emulate: Membership on an entity's Board of Directors or advisory committees; BOA Biomedical: Membership on an entity's Board of Directors or advisory committees; Freeflow Medical Devices Inc: Membership on an entity's Board of Directors or advisory committees.

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.

Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Identification and characterization of drug resistance mechanisms in cancer cells against Aurora kinase inhibitors CYC116 and ZM447439

CYC116 is a selective Aurora kinase inhibitor that has been tested in a Phase I study in patients with advanced solid tumors. Although CYC116 has shown desirable preclinical efficacy, the potential for emergence of resistance has not been explored. We established several CYC116 resistant clones from isogenic HCT116 p53+/+ and HCT116 p53−/− cell line pairs. We also generated resistant clones towards ZM447439 (quinazoline derivative), a model Aurora inhibitor. The selected clones were 10-80 fold resistant to CYC116 and cross-resistant to other synthetic Aurora inhibitors including AZD1152, VX-680, and MLN8054. Resistant clones displayed multidrug resistant phenotypes, tested by using 13 major cytostatics. All clones were highly resistant to etoposide followed by other drugs. Interestingly, all CYC116 clones but not ZM447439 became polyploid. ZM447439, but not CYC116 induced three novel mutations in Aurora B. Leu152Ser significantly affected ZM447439 binding, but not CYC116. Gene expression studies revealed differential expression of more than 200 genes. Some of these genes expression profiles were also observed in CYC116 resistant primary tumors. Bcl-xL (BCL2L1) was found to be overexpressed in CYC116 clones and its knockdown resensitized the p53+/+ resistant clone to CYC116. Finally Bcl-xL overexpressing p53+/+ CYC116 clones were highly sensitive to navitoclax (ABT-263) compared to parent cells. The data shed light on the genetic basis for resistance to Aurora kinase inhibitors which could be used to predict clinical response, to select patients who might benefit from therapy and to suggest suitable drug combinations for a particular patient population.

Screening of drug efficacy of Rosmarinic Acid derivatives as Aurora kinase inhibitors by computer aided drug design method

Background: Aurora kinases (AKs) belong to serine/threonine kinase family, play a crucial role in regulating the cell cycle. Therefore, AKs are the hopeful target for anticancer therapies and these finding have appreciated researchers to rigorous hunting of small molecule aurora kinase inhibitors, not only for research articles but also use as therapeutic agent. Objective: The present study helps us to identify and screen best phytochemicals as potent inhibitors against AKs. These potent inhibitors are coming from various substitution of rosmarinic acid (RA). Methods: In this paper, we choose different tested derivative compounds for designing anticancer drugs by substituting various functional groups of standard drug RA. In silico studies were carried out, in an effort to appreciate better drug candidature of some of these derivative compounds. This study wasperformed on 56 derived compounds of standard RA. DFT study was done using UB3LYP/6-311G++G(d,p) basis set to study HOMO-LUMO energies, dipole moments, using Gaussian16 suite. Some of the derived parameters, like ionization potential, electron affinity, softness-hardness, chemical potential and electrophilicity index were noted. Docking study was performed with AKs inhibiting receptor using AutoDock 4.2. ADME prediction was done with preADMET web tool. Molecular descriptor properties were predicted with molinspiration and OSIRIS property explorer. Results: Out of 56 derivatives, 11 have passed all the rules of drug candidature, to serve as best AKs inhibitor, in a theoretical manner. Conclusions: This study should be supported a new proposal to explore future studies with these 11 compounds against cancer.