Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRASG12D 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, which is one of the main drivers of 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 1498 single cells were analyzed. From these cells, 3140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.

Automated summary

Mutations in the KRAS gene are common drivers of cancer in humans. This study discovered a promising compound, MRTX1133, that inhibits the activity of KRAS(G12D) mutant proteins in pancreatic cancer cells. Through proteomics and metabolomics analysis, it was found that after 48 hours of treatment, the compound showed different levels of effectiveness in reducing the abundance of KRAS protein in different cell populations.