We performed single-cell RNA sequencing for 3,115 primary bladder cancer cells (BC159-T#3) and patient-derived xenograft cells (BC159-T#3-PDX-vehicle and BC159-T#3-PDX-tipifarnib). Matched time-series bulk tumor tissues were also sequenced using whole exome target probe (WES) and whole transcriptome target probe (WTS).

Personalized therapy to covercome treatment resistance could be developed by experimental analysis of cell-type specific transcriptomal changes of a cancer. Here, we applied single-cell mRNA sequencing techniques to a chemotherapy-resistant urothelial cell bladder cancer and elucidated cancer-cell specific overexpression of an HRAS mutant. Clinically, tipifarnib, a HRAS-targeting agent, showed dramatic effects on the cancer although development of resistance followed. Interestingly, the resistance was accompanied by upregulation of PD-L1 in cancer cells, which was translated to atezolizumab, a immune checkpoint inhibitor. The immunotherapy also showed clinical responses to prolong the survival of the patient. Altogether, this study demonstrated clinical applicability of single cell-level transcriptome analysis to find personalized salvage treatment options for cancers that have treatment resistance.