Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets

Beyond habitat requirements: individual fine-scale site fidelity in a colony of the Galapagos sea lion (Zalophus wollebaeki) creates conditions for social structuring

Wolf JBW, Trillmich F. Beyond habitat requirements: individual fine-scale site fidelity in a colony of the Galapagos sea lion (Zalophus wollebaeki) creates conditions for social structuring. Oecologia. 2007;152(3):553-567.Site fidelity has been widely discussed, but rarely been related explicitly to a species' social context. This is surprising, as fine-scale site fidelity constitutes an important structural component in animal societies by setting limits to an individual's social interaction space. The study of fine-scale site fidelity is complicated by the fact that it is inextricably linked to patterns of habitat use. We here document fine-scale site fidelity in the Galapagos sea lion (Zalophus wollebaeki) striving to disentangle these two aspects of spatial behaviour. Regardless of sex and age, all individuals used small, cohesive home ranges, which were stable in size across the reproductive and non-reproductive season. Home ranges showed a large individual component and did not primarily reflect age- or sex-specific habitat requirements. Site specificity could be illustrated up to a resolution of several metres. Long-term site fidelity was indicated by home range persistence over 3 years and the degree of site fidelity was unaffected by habitat, but showed seasonal differences: it was lower between reproductive and non-reproductive periods than between reproductive seasons. We further examined static and social interaction within mother-offspring pairs, which constitute a central social unit in most mammalian societies. Regardless of the occupied habitat type, adult females with offspring had smaller home range sizes than non-breeding females, demonstrating the importance of spatial predictability for mother-offspring pairs that recurrently have to reunite after females' foraging sojourns. While social interaction with the mother dropped to naught in both sexes after weaning, analysis of static interaction suggested female-biased home range inheritance. Dispersal decisions were apparently not based on habitat quality, but determined by the offspring's sex. We discuss the implication of observed fine-scale site fidelity patterns on habitat use, dispersal decisions and social structure in colonial breeding pinnipeds