Development of resistance to type II JAK2 inhibitors in MPN depends on AXL kinase and is targetable.

PURPOSE Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Since clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition. METHODS MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC-/RNA-sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice. RESULTS MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NSG mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Since inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL-MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL-MAPK. CONCLUSIONS We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN

External auditory canal atresia - Our methods to speed up procedure with maximal safety and efficacy

Introduction: External auditory canal atresia is a rare congenital disorder which affects one or both ears. With a conductive haring loss of 60 dB, even unilateral atresia affects hearing related social skills. Reconstruction surgery is difficult and hazardous and functional results may be insufficient thus making bone-conduction hearing aids the first-line therapy nowadays.Methods: Two 6-year-old children with unilateral cartilaginous and bony external auditory canal atresia were enrolled. Investigation involved physical examination, pure-tone and speech audiometry, and high-resolution computed tomography with three dimensional reconstructions. Reconstruction surgery from retroauricular approach comprised maximal enlargement of the tympanic and mastoid cavities while the facial nerve canal was preserved. The cavities were closed with an adapted conchal cartilage, the medial part of which was made thinner to serve as a tympanic membrane.Results: Postoperative period and facial nerve function were normal. Hearing improvement reached the level above the social threshold, with which the subjects were absolutely satisfied. The reconstructed auditory canal remained stable and widely patent during the follow-up period of 1 year. Conclusion: The authors highlight that surgical reconstruction of the external auditory canal is safe and effective and involves reasonably short surgical time. Stable audiological benefits improve patients' satisfaction and quality of life without the necessity of hearing aids. The procedure is essentially assisted by careful preoperative imaging techniques and intraoperative facial nerve monitoring. Further improvement in hearing levels can be reached in a second sit by thinning down and readapting the conchal cartilage which serves as a tympanic membrane.Supported by: clinical associatesDer Erstautor gibt keinen Interessenkonflikt an