In this study, we report a number of unexpected and serendipitous findings including hemizygous passenger co-deletion of SCD with phosphatase and tensin homolog (PTEN) on chromosome 10, methylation of the trans-SCD allele in a subset of patients, intrinsic resistance of lines derived from this subset to SCD inhibitors despite retention of residual SCD activity, and discovery of a universal mechanism of SCD inhibitor acquired resistance in cancer. Here, PTEN is linked to cancer.