FAM111B Suppression Enhances Sensitivity to Gemcitabine in Pancreatic Cancer Through Intracellular pH Regulation.

Pancreatic cancer remains a highly lethal disease, largely attributed to the rapid development of resistance against standard chemotherapy regimens. Although an acidic tumor microenvironment (TME) has been implicated in this resistance, the molecular mechanisms involved are not fully understood. In this study, we identified Family with Sequence Similarity 111 Member B (FAM111B) as significantly upregulated in pancreatic cancer cells under acidic conditions through RNA sequencing and validated. Functional analyses revealed that FAM111B regulates intracellular pH (pHi). Moreover, combining gemcitabine with α-cyano-4-hydroxycinnamic acid, a lactate transporter inhibitor known to decrease pHi, markedly suppressed pancreatic cancer cell viability compared to gemcitabine alone, thereby enhancing the sensitivity under acidic conditions in both in vitro and in mouse xenograft models. Clinically, elevated FAM111B expression correlated with significantly poorer overall survival in pancreatic cancer patients receiving gemcitabine-based chemotherapy (median OS: 2.05 vs. 3.66 years, p = 0.038). Multivariate analysis identified FAM111B expression as an independent predictor of poor prognosis (HR = 3.05, p = 0.032). These findings highlight the crucial role of FAM111B in maintaining pHi homeostasis under acidic TME conditions and contributing to gemcitabine resistance. Targeting FAM111B may represent a novel therapeutic strategy to overcome chemotherapy resistance and improve clinical outcomes in pancreatic cancer.