Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRASG12D Inhibitor MRTX1133.

Abstract

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 KRASG12D 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 KRASG12D 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.

• Authors: Benjamin C Orsburn
• Journal: Journal of proteome research (J Proteome Res) Vol. 22 Issue 12 Pg. 3703-3713 (Dec 01 2023) ISSN: 1535-3907 [Electronic] United States
• PMID: 37983312 (Publication Type: Journal Article)

Chemical References

• Proto-Oncogene Proteins p21(ras)
• KRASG12D inhibitor MRTX1133
• KRAS protein, human

Topics

• Humans
• Proto-Oncogene Proteins p21(ras) (genetics)
• Proteomics
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Mutation