Systems analysis of protein signatures predicting Cetuximab responses in KRAS, NRAS, BRAF and PIK3CA wild-type patient-derived xenografts models of metastatic colorectal cancer

Colorectal Cancer
23/07/2020

Int J Cancer. 2020 Jul 23. doi: 10.1002/ijc.33226. Online ahead of print.

ABSTRACT

Antibodies targeting the human epidermal growth factor receptor (EGFR) are used for the treatment of RAS wild-type metastatic colorectal cancer. A significant proportion of patients remains unresponsive to this therapy. Here, we performed a reverse phase protein array-based (phospho)protein analysis of 63 KRAS, NRAS, BRAF and PIK3CA wild-type metastatic CRC tumours. Responses of tumours to anti-EGFR therapy with cetuximab were recorded in patient-derived xenograft (PDX) models. Unsupervised


hierarchical clustering of pre-treatment tumour tissue identified three clusters, of which cluster C3 was exclusively composed of responders. Clusters C1 and C2 showed mixed responses. None of the three protein clusters showed a significant correlation with transcriptome-based subtypes. Analysis of protein signatures across all PDXs identified 14 markers that discriminated cetuximab-sensitive and -resistant tumours: PDK1 (S241), Caspase-8, Shc (Y317), Stat3 (Y705), p27, GSK-3β (S9), HER3, PKC-α (S657), EGFR (Y1068), Akt (S473), S6 Ribosomal Protein (S240/244), HER3 (Y1289), NF-κB-p65 (S536) and Gab-1 (Y627). Least absolute shrinkage and selection operator and binominal logistic regression analysis delivered refined protein signatures for predicting response to cetuximab. (Phospo-)protein analysis of matched pre- and post-treated models furthermore showed significant reduction of Gab-1 (Y627) and GSK-3β (S9) exclusively in responding models, suggesting novel targets for treatment. This article is protected by copyright. All rights reserved.