Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer

Abstract

Protein biomarkers are widely used in cancer diagnosis, prognosis, and prediction of treatment response. Here we introduce the use of targeted multiplex proteomics (TMP) as a tool to simultaneously measure a panel of 54 proteins involved in oncogenic, tumour suppression, drug metabolism and resistance, in patients with metastatic colorectal cancer (mCRC). TMP provided valuable diagnostic information by unmasking an occult neuroendocrine differentiation and identifying a misclassified case based on abnormal proteins phenotype. No significant differences in protein levels between unpaired primary and metastatic samples were observed. Four proteins were found differentially expressed in KRAS-mutant as compared to wild-type tumours (overexpressed in mutant: KRAS, EGFR; overexpressed in wild-type: TOPO1, TOP2A). Survival analyses revealed the association between mesothelin expression and poor overall survival, whereas lack of PTEN protein expression associated with lower progression-free survival with anti-EGFR-based therapy in the first-line setting for patients with RAS wild-type tumour. Finally, outlier analysis identified putative targetable proteins in 65% of patients lacking a targetable genomic alteration. Our data show that TMP constitutes a promising, novel molecular prescreening tool in mCRC to identify protein expression alterations that may impact on patient outcomes and more precisely guide patient eligibility to clinical trials with novel targeted experimental therapies.

EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

“…We found that expression of EGFR and its dimerization partners is common in KRAS G12C CRC and NSCLC clinical samples. Basal EGFR expression, as measured by immunohistochemistry or mass spectrometry (28,29), has not been associated with EGFR inhibitor sensitivity in CRC, and indeed we find no clear difference between receptor expression levels by lineage or in the subset of CRC and NSCLC patients treated with AMG510. In cell line models, however, we are able to assess activated RTK levels and we find that the degree of this dependency on RTK signaling across KRAS G12C mutant tumors can be very different.…”

Effect of polysaccharide extract SPSS1 from Apostichopus japonicus spermary on HepG2 cells via iTRAQ‐based proteome analysis

“…Proteomics, as a valuable tool to unravel the biochemical changes, is rapidly developed and become a useful laboratory tool to improve cancer management from early detection to the exploitation of therapeutic strategies (Serna et al, 2019). iTRAQ (isobaric tags for relative and absolute quantitation) by a multiplexed set of reagents for quantitative protein analysis that place isobaric mass labels at the N termini and lysine side chains of peptides in a digest mixture, is an emerging quantitative proteomic method with great speed and accuracy (Guo et al, 2016).…”

An Introduction to Advanced Targeted Acquisition Methods

“…Such developments will facilitate research by providing detailed functional information, like for example the activity of specific pathways (65,67). On the other hand, less complex but more robust targeted acquisition approaches will likely become more relevant in clinical settings and could complement antibody-based detection for diagnosis and stratification (88)(89)(90). Biochimica Et Biophysica Acta Bba -Proteins Proteom 1844, 917-926 33.…”