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Proteomics uncover EPHA2 in cetuximab resistant colorectal cancer cell lines as a potential novel therapeutic target

ABSTRACT: In metastatic colorectal cancer (mCRC), primary and acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), were shown to be frequently caused by activating alterations in RAS genes (KRAS or NRAS). To this day no efficient second-line treatment options have emerged to treat mCRC upon emergence of acquired KRAS alterations. In order to uncover potential targets for second-line targeted therapies, we used mass spectrometric proteomics to shed light on kinome reprogramming in an established model of acquired, KRAS associated CET resistance. This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly a common theme in all investigated resistant cell lines was the upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of cell migration. Expectedly resistant cell lines displayed increased migration (p<0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (p<0.001), ephrin-A1 stimulation (p<0.001), dasatinib (p<0.01) or anti-EPHA2 antibody treatment (p<0.001), identifying it as an actionable target in CET resistant mCRC. These results highlight EPHA2 and its role in KRAS mutated acquired CET resistance in mCRC and identify it as a potential target for the development of future precision medicine therapies.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Anna Jarzab

LAB HEAD: Bernhard Kuster

PROVIDER: PXD022072 | Pride | 2023-03-10

REPOSITORIES: Pride

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Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

Torlot Lucien L Jarzab Anna A Albert Johanna J Pók-Udvari Ágnes Á Stahler Arndt A Holch Julian Walter JW Gerlinger Marco M Heinemann Volker V Klauschen Frederick F Kirchner Thomas T Kumbrink Jörg J Küster Bernhard B Jung Andreas A

Journal of cancer research and clinical oncology 20221119 2

<h4>Background</h4>In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance.<h4>Methods</h4>To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome r ...[more]

PMID: 36401637

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Dataset Information

Proteomics uncover EPHA2 in cetuximab resistant colorectal cancer cell lines as a potential novel therapeutic target

Publications

Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

Similar Datasets

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