Metabolomic, proteomic and single cell proteomic analysis of cancer cells treated with the KRAS(G12D) inhibitor MRTX1133

Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRAS(G12D) mutant proteins, one of the main drivers in pancreatic cancer. To better understand the mechanism of action of this compound I performed both proteomics and metabolomics on four KRAS(G12D) mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1,498 single cells were analyzed. From these cells 3,140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 hours of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing total abundance of the KRAS protein in each respective cell, results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at the www.massive.ucsd.edu at accessions PXD039597, PXD039601 and PXD039600.