Fig 3.

Molecular rationale for using ruxolitinib to treat the sarcoma in patient 1. (A) Candidate pathway that drove tumorigenesis in patient 1 was reconstructed on the basis of outlier analysis, differential expression analysis compared with normal tissues, copy number information, and literature mining (Appendix Methods). Both EWSR1-ATF1 and receptor tyrosine kinases NTRK1 and ALK can contribute to the activation of IL6/JAK/STAT3 signaling. All gene expression outliers depicted in the figure (gene names written in red font) were significant in all three comparisons: patient 1 versus all cancers, patient 1 versus lung adenocarcinomas, and patient 1 versus sarcomas. JAK1, the molecular target of ruxolitinib, is indicated with a yellow lightning bolt. (B) The tumor in patient 1 expresses JAK1 at a strikingly higher level than those seen in all 10,668 tumors, which are represented by 38 tumor types studied by the TCGA¹¹ and TARGET (denoted PANCAN),¹² including lung adenocarcinomas (LUADs) and sarcomas (SARCs). (C) JAK1 is an attractive molecular target for patient 1’s tumor because it is downstream of the EWSR1-ATF1 fusion and the activate receptor tyrosine kinases (RTKs). It was also identified as over expressed by gene expression outlier analysis.