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Simple Summary: RAS oncoproteins are considered undruggable cancer targets. Nearly 15% of cases of bladder cancer have a mutation of HRAS. The active HRAS contributes to the tumor progression and the risk of recurrence. Using our novel gene expression screening platform, pterostilbene was identified to sensitize cisplatin-resistant bladder cancer cells with HRAS alterations via RAS-related autophagy and cell senescence pathways, suggesting a potentially chemotherapeutic role of pterostilbene for cisplatin treatment of human bladder cancer with oncogenic HRAS. Pterostilbene is a safe and readily available food ingredient in edible plants worldwide. Exploiting the principle of combination therapy on pterostilbene-enhanced biosensitivity to identify undruggable molecular targets for cancer therapy may have a great possibility to overcome the cisplatin resistance of bladder cancer. Our data make HRAS a good candidate for modulation by pterostilbene for targeted cancer therapy in combination with conventional chemotherapeutic agents cisplatin plus gemcitabine. Analysis of various public databases revealed that HRAS gene mutation frequency and mRNA expression are higher in bladder urothelial carcinoma. Further analysis revealed the roles of oncogenic HRAS, autophagy, and cell senescence signaling in bladder cancer cells sensitized to the anticancer drug cisplatin using the phytochemical pterostilbene. A T24 cell line with the oncogenic HRAS was chosen for further experiments. Indeed, coadministration of pterostilbene increased stronger cytotoxicity on T24 cells compared to HRAS wild-type E7 cells, which was paralleled by neither elevated apoptosis nor induced cell cycle arrest, but rather a marked elevation of autophagy and cell senescence in T24 cells. Pterostilbene-induced autophagy in T24 cells was paralleled by inhibition of class I PI3K/mTOR/p70S6K as well as activation of MEK/ERK (a RAS target) and class III PI3K pathways. Pterostilbene-induced cell senescence on T24 cells was paralleled by increased pan-RAS and decreased phospho-RB expression. Coadministration of PI3K class III inhibitor 3-methyladenine or MEK inhibitor U0126 suppressed pterostilbene-induced autophagy and reversed pterostilbene-enhanced cytotoxicity, but did not affect pterostilbene-elevated cell senescence in T24 cells. Animal study data confirmed that pterostilbene enhanced cytotoxicity of cisplatin plus gemcitabine. These results suggest a therapeutic application of pterostilbene in cisplatin-resistant bladder cancer with oncogenic HRAS. [ABSTRACT FROM AUTHOR]