Knockdown of KLF5 sensitizes cells to cisplatin. (A) Relative mRNA expression levels of PRNP and KLF5 in response to indicated treatment HT29 cells and (B) SW620 cells. (Data normalized to GAPDH ± SEM and significance measured by two‐tailed Student's t‐test ***P < 0.001) (C) Targeted knockdown of KLF5 in HT29 and SW620 cells. (D) Targeted knockdown of PrPC in HT29 and SW620 cells. (E) Cisplatin IC50 in HT29 cells and (F) SW620 cells following PrPC, KLF5, or double knockdown determined by MTS. (Data compared to SCR control ± SEM and significance measured by two‐tailed Student's t‐test ***P < 0.001, *P < 0.05) SCR, nontargeting scrambled; PRNPsi, PrPC knockdown; KLF5si, KLF5 knockdown; DKO, double (PrPC and KLF5) knockdown. (G) A schematic showing the proposed EGFR signaling cascade in cisplatin‐sensitive and cisplatin‐resistant cells. The point of action of cisplatin, gefitinib, and p38 MAPK inhibitor is indicated.