24 research outputs found
<html>Efficacy of the combination of MEK and CDK4/6 inhibitors <i>in vitro</i> and <i>in vivo</i> in KRAS mutant colorectal cancer models</html>
Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo
Development of novel cellular histone-binding and chromatin-displacement assays for bromodomain drug discovery
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Activation of gp130 signaling in vivo by the ILā6 superāagonist Kā7ā/āDā6 accelerates repopulation of lymphoid organs after irradiation
Stimulation of the gp130 signaling pathway by ILā6 is known to contribute significantly to hematopoietic expansion in vitro, mostly in combination with other cytokines. In the present study we have investigated whether a similar effect can be observed also in vivo using shortterm assays in which irradiated mice were analyzed for repopulation of lymphoid organs. Mice were injected with a combination of soluble ILā6RĪ± either with wildātype (wt) human ILā6 or with an ILā6 variant, called Kā7ā/āDā6, that shows a 70āfold higher ILā6RĪ± affinity. We observed that while wt ILā6 was able to induce a partial effect only in combination with ILā3, Kā7ā/āDā6 bypassed the need for ILā3 and yielded complete recovery. In lethally irradiated mice reconstituted with syngeneic bone marrow cells Kā7ā/āDā6 strongly accelerated the repopulation of thymus and spleen and hastened blood neutrophil recovery. These results underscore the potential of the gp130 signaling pathway in hematopoietic reconstitution after myeloablative regimens and open the possibility to fully exploit it with a superāactive ILā6 variant