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Cell specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient or tumor specific variations, we constructed cell line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting ppERK and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Ductal Cell, Cell Culture

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Kieran Wynne

LAB HEAD: Boris Kholodenko

PROVIDER: PXD047912 | Pride | 2024-09-03

REPOSITORIES: pride

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			Action	DRS
	230623kw_TSeverin_Prot_19_S1-A1_1_15240.d.zip	Other
	230623kw_TSeverin_Prot_19_S1-A2_1_15241.d.zip	Other
	230623kw_TSeverin_Prot_21_S1-A3_1_15242.d.zip	Other
	230623kw_TSeverin_Prot_21_S1-A4_1_15243.d.zip	Other
	230623kw_TSeverin_Prot_22_S1-A5_1_15244.d.zip	Other

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Project description:Pancreatic ductal adenocarcinoma (PDAC) suffers from lack of an effective diagnostic method, limiting improvement in patient survival. Although the FDA-approved biomarker CA19-9 has been used for detection and surveillance of PDAC, its clinical utility is generally regarded to be limited due to its suboptimal diagnostic performance. Liquid chromatography-mass spectrometry (LC-MS) has emerged as a burgeoning technology in clinical proteomics, and identified a plethora of protein biomarker candidates for PDAC. Yet few if any has successfully transitioned into clinical practice. This translational standstill is owed partly to the limited considerations of practical needs and perspectives of clinical implementation in the course of a biomarker pipeline, such as demonstrating analytical validity of proposed biomarkers, which is critical to turning research-grade assays to clinical-grade tests. Here, we developed a fit-for-purpose multi-marker panel for PDAC diagnosis by consolidating analytically robust biomarkers as well as employing a relatively simple LC-MS method. In the discovery phase, we systematically collected putative biomarkers from both in-house proteomics data and the large volume of literature documenting PDAC biomarkers. In the verification phase, we developed a multiple-reaction monitoring (MRM)-MS-based proteomic assay using surrogate peptides that passed stringent analytical validation criteria. Given the intended use of our panel (i.e., primary screening), we adopted a high-throughput protocol including short gradient (<10 min) and simple sample preparation (no depletion or enrichment steps). To further facilitate clinical implementation, we performed verification of our panel on serum samples, which are usually the preferred biospecimen available in clinical settings. We developed a stacking ensemble model based on our final panel of 12 protein biomarkers combined with CA19-9, which showed improved diagnostic performance compared to using CA19-9 alone (AUC 0.919 and 0.830, respectively). A large-scale clinical validation study is underway to demonstrate the clinical validity of our panel.

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Cell specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

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