Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma

Resistance to gemcitabine is the main challenge of chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Hence, the development of a response signature to gemcitabine is essential for precision therapy of PDAC. However, existing quantitative signatures of gemcitabine are susceptible to batch effects and variations in sequencing platforms. Therefore, based on within‐sample relative expression ordering of pairwise genes, we developed a transcriptome‐based gemcitabine signature consisting of 28 gene pairs (28‐GPS) that could predict response to gemcitabine for PDAC at the individual level. The 28‐GPS was superior to previous quantitative signatures in terms of classification accuracy and prognostic performance. Resistant samples classified by 28‐GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level and higher‐fidelity DNA damage repair compared with sensitive samples. In addition, we found that gemcitabine combined with phosphoinositide 3‐kinase (PI3K) inhibitor may be an alternative treatment strategy for PDAC. Single‐cell analysis revealed that cancer cells in the same PDAC sample showed both the characteristics of sensitivity and resistance to gemcitabine, and the activation of the TGFβ signalling pathway could promote progression of PDAC. In brief, 28‐GPS could robustly determine whether PDAC is resistant or sensitive to gemcitabine, and may be an auxiliary tool for clinical treatment. Using within‐sample relative expression ordering of pairwise genes, we developed a qualitative gemcitabine signature containing 28 gene pairs, named 28‐GPS. The 28‐GPS outperformed previous signatures in classification accuracy and prognostic performance for pancreatic ductal adenocarcinoma (PDAC). Compared with gemcitabine‐sensitive PDAC samples, gemcitabine‐resistant PDAC samples classified by 28‐GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level and higher‐fidelity DNA damage repair.