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.