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Mancias Lab - Pancreatic Cancer Research

Mancias Laboratory
PANCREATIC CANCER RESEARCH

New lab publication in Cell Reports on 'Defining and Targeting Adaptations to Oncogenic KRAS-G12C Inhibition Using Quantitative Temporal Proteomics'

3/31/2020

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In this study published in Cell Reports and led by co-first authors Naiara Santana-Codina, PhD and Amrita Singh Chandhoke, PhD, the lab uses a quantitative temporal proteomics workflow to identify proteomic adaptations to short and long-term KRAS-G12C inhibition (KRASi) in lung and pancreatic adenocarcinoma. 

In this study, we quantified 10,805 proteins, representing the most comprehensive KRASi proteome (https://manciaslab.shinyapps.io/KRASi/). Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. Based on these proteomic data, we identify potent combinations of KRASi with phosphatidylinositol 3-kinase (PI3K), HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using quantitative temporal proteomics, we comprehensively characterize adaptations to KRASi and identify combinatorial regimens with potential therapeutic utility. 

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Mancias Lab is awarded a R01 from the NIH/NIDDK!

3/1/2020

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This past week we received our official notice of award for our R01 submission to the NIH/NIDDK! The lab is excited to study 'The role of NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosis.'  From our project summary:

 Specific Aim 1 will define the biochemical mechanisms regulating NCOA4 activity in cells using an integrated quantitative proteomic and cell biologic experimentation workflow. In specific aim 2, we will determine the temporal and spatial dependency of ferritinophagy in vivo for regulating systemic iron homeostasis and erythropoiesis using novel mouse models of NCOA4 knockout and over-expression. Finally, specific aim 3 will focus on examining a role for NCOA4 in regulating sensitivity to ferroptosis in vivo under pathophysiologic conditions, including pancreatic cancer. Together, the proposed in vitro and in vivo studies will identify fundamental roles of NCOA4 in sensing and responding to iron deficiency and overload and determine the utility of pursuing NCOA4 as a therapeutic target for multiple iron-related disorders.

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