Biology subjects

Petricoin, E.

Publications and source records attributed to Petricoin, E..

6 recordsLinked to original sources

bioRxiv2026

Vertical inhibition of the autophagy pathway impairs growth and enhances sensitivity to mTORC1 inhibition in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is dependent on autophagy for growth. Chloroquine/Hydroxychloroquine (CQ/HCQ), the sole FDA-approved autophagy inhibitors, have shown limited clinical efficacy as cancer therapies. To identify approaches to improve PDAC response to CQ, we performed a CQ-anchored, CRISPR-Cas9 mediated loss-of-function screen. We identified that the loss of genes encoding proteins upstream in the autophagy pathway enhanced CQ-mediated growth suppression. This indicated that simultaneous targeting of two distinct nodes of the same pathway, vertical inhibition, may be a more effective strategy than single node inhibition. We demonstrated that genetic loss or pharmacological inhibition of VPS34, a protein necessary for autophagosome nucleation, sensitized PDAC cells to inhibitors of the terminal stage of the autophagy pathway, including CQ and an inhibitor of PIKfyve. We extended this concept to the initiation complex and demonstrated that ULK1/2 inhibition synergized with CQ and PIKfyve inhibition to impair PDAC cell growth and increase apoptosis. Anticipating mechanisms of resistance to vertical autophagy inhibition, we performed reverse-phase protein array profiling and identified that vertical inhibition of the autophagy pathway resulted in enhanced activation of the PI3K-AKT-mTORC1 signaling pathway. Increased mTORC1 signaling resulted in heightened sensitivity to bi-steric mTORC1 inhibition in both cell line and organoid models of PDAC. This study identifies novel anti-autophagy inhibitor combinations that may improve the clinical efficacy of autophagy inhibition for PDAC treatment. IMPLICATIONSVertical inhibition of the autophagy pathway reduces pancreatic cancer cell growth, increases apoptosis, and enhances sensitivity to mTORC1 inhibition; thereby representing a novel therapeutic strategy for autophagy-driven pancreatic cancer.

Cancer Biology↗

bioRxiv2025

Dordaviprone/ONC201 Activation of the ClpP Mitochondrial Protease Inhibits the Growth of KRAS-Mutant Pancreatic Cancer and Overcomes RAS Inhibitor Resistance

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS-driven oncogenic signaling and tumor growth. Blockade of the KRAS ERK-MAPK pathway via small molecule direct RAS inhibitors has shown clinical promise, but intrinsic and acquired resistance limit the efficacy of these inhibitors as single agents. To identify potential combination strategies, we first assessed the ability of dordaviprone/ONC201, an FDA-approved agent, to inhibit PDAC cell and organoid growth. We observed that ONC201 reduced the growth of a broad panel of KRAS-mutant PDAC cell lines, and that the expression of mitochondrial protease ClpP was required for this efficacy. Mechanistically, we observed that treatment with ONC201 led to inhibition of mitochondrial respiration, causing a compensatory increase in glycolysis. Furthermore, ONC201 caused ClpP-dependent activation of PI3K-AKT-mTOR signaling and concurrent PI3K and mTOR inhibition further enhanced ONC201 growth suppression. ONC201 demonstrated an additive effect when combined with a RAS(ON) multi-selective inhibitor RMC-7977 in PDAC cells and organoids. Finally, PDAC cell lines with acquired resistance to RMC-7977 or KEAP1 loss-driven resistance retained sensitivity to ONC201. We propose that concurrent treatment with ONC201 may delay onset of resistance to RAS inhibitor therapy. Statement of SignificanceClpP activation by dordaviprone/ONC201 suppressed PDAC cell growth and overcame resistance to the RAS(ON) multi-selective inhibitor RMC-7977, providing support for investigating this combination as a potential combination treatment for KRAS-mutant pancreatic cancer.

cancer biology↗

bioRxiv2025

Preliminary insights into salivary proteomic versus targeted biomarker profiles associated with acute physical fatigue

Introduction: Physical fatigue is a key determinant of operational readiness in tactical athletes. Hormonal, immune, and enzymatic biomarkers have been proposed for fatigue assessment, but reliability can be affected by external factors. Therefore, this study aimed to compare targeted stress-related biomarkers, proteins identified via untargeted salivary proteomics, and a combined panel of both for classifying acute physical fatigue. Methods: Ten recreationally active adults (6M, 4F) completed a fatiguing protocol within a 3-day sample collection window. Saliva samples were analyzed for targeted biomarkers via commercial immunoassays and proteins via untargeted liquid chromatography-mass spectrometry. Targeted, protein, and combined panels were identified using nested leave-one-subject-out cross-validation with FDR correction and stability selection, then classified via ridge-penalized logistic regression. Models were extended across the full protocol to evaluate classification of fatigue onset, rest, and recovery states. Results: A candidate identified protein (C1S) achieved slightly higher classification accuracy (80%) relative to a panel of targeted biomarkers (IgA and UA 70%), with superior sensitivity but similar specificity. In comparison, the combined panel, spanning immune (IgA), oxidative/metabolic (UA), complement (C1S), and cellular stress-related (ANG) outperformed both single-platform models with 90% accuracy, sensitivity, and specificity. Conclusions: Improved classification accuracy observed with the inclusion of candidate salivary proteins provide preliminary support for non-invasive proteomic monitoring of fatigue in tactical settings, and in particular the combination of complementary targeted and proteomic panels to capture a more complete physiological signature of acute fatigue. Future studies should validate these findings in larger, more diverse populations and assess applicability for chronic fatigue monitoring.

physiology↗

bioRxiv2024

Impact of genomic background and developmental state on signaling pathways and response to therapy in Glioblastoma patient-derived cells

Glioblastoma (GBM) tumors represents diverse genomic epigenomic, and transcriptional landscapes, with significant intratumoral heterogeneity that challenges standard of care treatments involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed targeted proteomics to assess the response of a genomically-diverse panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation, growth factor withdrawal and traditional high fetal bovine serum culture. Our findings revealed a complex crosstalk and co-activation of key oncogenic signaling in CSCs and diverse patterns of response to these external stimuli. Using RNA sequencing and DNA methylation, we observed common adaptations in response to astrocytic differentiation of CSCs across genomically distinct models, including BMP-Smad pathway activation, reduced cholesterol biosynthesis, and upregulation of extracellular matrix components. Notably, we observed that these differentiated CSC progenies retained a subset of stemness genes and the activation of cell survival pathways. We also examined the impact of differentiation state and genomic background on GBM cell sensitivity and transcriptional response to TMZ and RT. Differentiation of CSCs increased resistance to TMZ but not to RT. While transcriptional responses to these treatments were predominantly regulated by p53 in wild-type p53 GBM cells, its transcriptional activity was modulated by the differentiation status and treatment modality. Both mutant and wild-type p53 models exhibited significant activation of a DNA-damage associated interferon response in CSCs and differentiated cells, suggesting this pathway may play a wider role in GBM response to TMZ and RT. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

cancer biology↗

bioRxiv2022

The potentiative cytotoxic effect of IGF1R and EGFR inhibition on the Head and Neck Cancer Proteome

Head and neck cancers are the sixth most common cancer worldwide. Combinatorial targeted therapy has the potential to reduce drug resistance and increase cytotoxicity to head and neck squamous cell carcinoma (HNSCC). Using drug combinations is especially important when targeting the epidermal growth factor receptor (EGFR) since we previously demonstrated that activation of the insulin-like growth factor 1 receptor (IGF1R) is a mechanism for resistance against EGFR inhibition and that a combination of an IGF1R inhibitor, BMS754807, and an EGFR inhibitor, BMS599626, robustly inhibited the growth of HNSCC cell lines in vitro. To examine the mechanism of cytotoxicity, we performed protein pathway activation mapping via reverse phase protein array (RPPA) analysis of 145 proteins and phosphoproteins in five HNSCC cell lines to map key proteins and phosphoproteins important in tumorigenesis. By performing principal component analysis, calculating log fold changes, and constructing protein networks, we were able to provide evidence to support the hypothesis that the combination of IGF1R and EGFR inhibitors has a potentiative effect on inhibiting receptor tyrosine kinase signaling. The effects of the individual drugs are amplified, demonstrating that the combination more robustly inhibits the pathways of both receptors.

cancer biology↗

bioRxiv2022

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this novel class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.

cancer biology↗