HPB
Zachary Gao, MD
Research Resident
Baylor College of Medicine
Houston, Texas, United States
Zachary Gao, MD
Research Resident
Baylor College of Medicine
Houston, Texas, United States
Zachary Gao, MD
Research Resident
Baylor College of Medicine
Houston, Texas, United States
Jiangling Dong, PhD
Postdoctoral Researcher
Baylor College of Medicine, United States
Harinarayanan Janakiraman, PhD
Staff Scientist
Baylor College of Medicine, United States
Jasmine Choi, BS
Research Technician
Baylor College of Medicine, United States
Derek Erstad, MD
Assistant Professor
Baylor College of Medicine, Department of Surgery, United States
William Fisher, MD
Professor
Baylor College of Medicine, Department of Surgery, United States
George Van Buren, MD
Associate Professor
Baylor College of Medicine, Department of Surgery, United States
Sung Wook Kang, PhD
Research Fellow
Baylor College of Medicine, United States
Hyun-Sung Lee, MD, PhD
Associate Professor
Baylor College of Medicine, United States
.jpg "E. Ramsay Camp, MD photo")
E. Ramsay Camp, MD
Professor
Baylor College of Medicine
Houston, TX, United States
Pancreatic adenocarcinoma (PDAC) holds a less than 10% five-year overall survival rate, attributed partly to chemoresistance. Current regimens are selected based on patients’ performance status and molecular strategies to enhance FOLFIRINOX (FFX) response have not been established. Personalization strategies have not been incorporated into practice yet hold significant promise. We hypothesize that developing a FFX-resistant gene signature could refine prognosis and predict response.
Methods: Two oxaliplatin-resistant (Oxa-R) PDAC cell lines were established by exposing parental murine KPC and human Panc-1 cell lines to incremental repeated doses of oxaliplatin. After RNA sequencing, we identified a gene signature indicative of chemoresistance. We assessed the prognostic and predictive relevance of this signature using data from the TCGA (n=177), CPTAC (n=127), QCMG (n=96), COMPASS (n=194), and our institutional cohort (n=33). To evaluate this signature's impact on chemotherapy-specific survival, we analyzed the COMPASS cohort, comprising pre-treatment data of patients treated with either FFX or gemcitabine, and our institutional cohort, comprising post-treatment data from patients administered neoadjuvant FFX.
Results:
We identified a set of 77 genes distinguishing parental (oxaliplatin-sensitive; Oxa-S) and Oxa-R KPC and Panc-1 cell lines (A-B). Gene set enrichment analysis indicated Oxa-R cells prominently featured activated G2M checkpoint, epithelial-to-mesenchymal transition, E2F targets, and Wnt-β-catenin pathways, whereas Oxa-S cells predominantly exhibited early estrogen response and TNF-alpha signaling (C). PDAC patients predicted to the Oxa-R group had notably worse overall survival compared to the Oxa-S group (D, E). Subgroup analysis of the COMPASS cohort revealed that the Oxa-S signature correlated with better survival in patients treated with FFX, underscoring the predictive potential of our chemoresistance signature (F). Additionally, patients of the Oxa-S cohort after neoadjuvant FFX therapy demonstrated superior survival compared to those without the treatment and to those with the Oxa-R cohort after neoadjuvant therapy, suggesting that the Oxa-R group primarily harbored chemoresistant cells after neoadjuvant therapy (G).
Conclusions: Our derived chemoresistance gene signature offers a promising tool for stratifying PDAC patients regarding FFX chemotherapy suitability. In addition, our findings support targeting the G2M checkpoint and E2F pathways to potentially counteract FFX resistance in PDAC patients.