Next-generation sequencing (NGS) to identify potential targets is becoming a common approach to refractory tumors. We describe a patient with a CIC-DUX4 sarcoma that harbored a patched homolog 1 (PTCH1) mutation, a mutation not previously reported in so-called Ewing family tumors. PTCH1 is part of the hedgehog signaling pathway. Basal cell carcinomas (BCC) commonly have PTCH1 mutations, and those with PTCH1 mutations are often responsive to therapy with the hedgehog pathway inhibitor vismodegib. The effect of any mutation in a gene important in cell growth and division is likely dependent upon the background biochemistry of the cell. In the current case, vismodegib was not effective. This case is the first report of a PTCH1 mutation in an Ewing family tumor and demonstrates that the utility of targeting a potential mutation may depend upon many factors, including other mutations in the signaling pathway, and importantly, also the background biochemistry of the malignant cell that may prevent effective treatment targeting.