Comparative Proteomic Profiling of Responses to Standard Systemic Treatment Regimens in Pancreatic Cancer

TL;DR

This study compares how two pancreatic cancer chemotherapy regimens affect proteins in cancer cells, revealing distinct biological effects that could help guide treatment choices.

Contribution

The study identifies regimen-specific proteomic programs in PDAC cells treated with FOLFIRINOX or gemcitabine/nab-paclitaxel.

Findings

FOLFIRINOX suppressed ribosome biogenesis and mitochondrial translation in PDAC cells.

Gemcitabine/nab-paclitaxel disrupted mitotic cytokinesis and lipid signaling in PDAC cells.

FOLFNX-altered proteins aligned with favorable prognostic signatures, while GEMPAC-associated proteins were linked to adverse profiles.

Abstract

What are the main findings?
FOLFIRINOX and gemcitabine/nab-paclitaxel induced distinct tumor-cell-intrinsic proteomic programs in PDAC cells.FOLFIRINOX suppressed ribosome biogenesis and mitochondrial translation, whereas gemcitabine/paclitaxel disrupted mitotic cytokinesis and lipid signaling.

FOLFIRINOX and gemcitabine/nab-paclitaxel induced distinct tumor-cell-intrinsic proteomic programs in PDAC cells.

FOLFIRINOX suppressed ribosome biogenesis and mitochondrial translation, whereas gemcitabine/paclitaxel disrupted mitotic cytokinesis and lipid signaling.

What are the implications of the main findings?
First-line PDAC chemotherapies are not biologically interchangeable despite having similar clinical efficacy.Regimen-specific molecular pathways provide a framework for developing predictive biomarkers of chemotherapy response.

First-line PDAC chemotherapies are not biologically interchangeable despite having similar clinical efficacy.

Regimen-specific molecular pathways provide a framework for developing predictive biomarkers of chemotherapy response.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of 13.3%. First-line treatment relies on two chemotherapy regimens, FOLFIRINOX (FOLFNX) or gemcitabine plus nab-paclitaxel (GEMPAC). However, direct clinical comparisons between these regimens have yielded inconsistent results across survival and toxicity endpoints, and the molecular basis of heterogeneous treatment responses remains poorly defined. To investigate regimen-specific tumor-cell-intrinsic mechanisms, we performed quantitative proteomic profiling of a primary PDAC-derived MIA PaCa-2 cell line following treatment with FOLFNX or GEMPAC. Differentially expressed proteins were analyzed using Gene Ontology, KEGG, and Ingenuity Pathway Analysis to define pathway-level alterations, and findings were contextualized using TCGA transcriptomic data. Proteomic analyses revealed that FOLFNX and GEMPAC engage in distinct cytotoxic programs. FOLFNX predominantly suppressed ribosome biogenesis and mitochondrial translation, consistent with sustained metabolic and biosynthetic stress, whereas GEMPAC preferentially disrupted mitotic cytokinesis and phosphatidylinositol phosphate biosynthesis, consistent with mitotic failure. Integration with TCGA data showed that FOLFNX-altered proteins aligned with favorable prognostic expression signatures, whereas GEMPAC-associated proteins were enriched among adverse profiles, reflecting engagement of distinct tumor-intrinsic programs. Together, these findings provide mechanistic insight into differential chemotherapy responses and establish a foundation for proteomics-based biomarkers to guide personalized chemotherapy selection in PDAC.

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