Background: Recently, we have successfully developed a transcriptomic signature that predicts the response to gemcitabine treatment in patients with localized pancreatic ductal adenocarcinoma (PDAC) (PMID: 36178036) and also in those with metastatic PDAC (PMID: 36496056). This was achieved by using an approach that combined several preclinical PDAC models. The FOLFIRINOX regimen (FFX) consisting of 5-Fluorouracil (5FU), Oxaliplatin, and Irinotecan is the more effective treatment option, but the high toxicity limits its use. In this study, we developed and analyzed three different transcriptomic signatures for the drugs composing FFX separately and evaluated their clinical utility. Methods: We combined the transcriptomic profile of 14 patients derived xenograft (PDX) and 31 patients derived cell cultures (PDC) with their corresponding chemotherapy response profiles. We developed predictive signatures for 5FU (5FUCore), Oxaliplatin (OxaliCore), and Irinotecan (IrinoCore), as previously reported for the GemCore signature (PMID: 36178036). They were then validated in three independent cohorts of patients: COMPASS (n = 94), Linehan (n = 28), and a new cohort of 87 advanced PDAC patients. Results: Three ICA components that reflect the chemotherapy response profiles for 5FU, oxaliplatin, and irinotecan were evaluated in the COMPASS cohort to determine their ability to identify sensitive patients in the FFX arm. Patients predicted as sensitive to each drug separately had a median overall survival (OS) of 77.6 (95% CI, 67.9-NR, P =0.02), 78.7 (95% CI, 57.6-NR, P= 0.002), and 70.4 (95% CI, 57.6-NR, P= 0.02) months for 5FU, oxaliplatin, and irinotecan, respectively. Notably, the model that integrated the group of sensitive patients to two or three drugs had the highest median OS in the COMPASS and Linehan cohorts with a HR of 0.25 (95% CI, 0.11-0.57; P < 0.001) and 0.11 (95% CI, 0.02-0.70; P= 0.019), respectively. Importantly, they also show a better objective response than the other groups (P= 0.009). In the advanced PDAC group, the signatures showed a strong ability to discriminate sensitive patients in the FFX arm with a median OS of 20.1 (95% CI, 2.3-NR, P= 0.006), 13.64 (95% CI, 9.57-NR, P= 0.003), and 15.87 (95% CI, 2.9-NR, P= 0.002) months for 5FU, oxaliplatin, and irinotecan, respectively. Finally, we evaluated the best combination of two drugs in the pooled group. Patients sensitive to both 5FU and oxaliplatin showed the best response with 60% of patients achieving partial response. Conclusions: The signatures developed provide a tool for predicting responsiveness to the individual therapeutic drugs of the FFX regimen. They may ultimately lead to the development of a personalized strategy for combined chemotherapy regimens, increasing efficacy and reducing toxicity in PDAC.