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Investigating protein kinase CK2 inhibition in BRAF colon cancer

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thesis
posted on 29.03.2022, 02:57 authored by Benjamin Brown
Within colon cancer, the BRAF mutation is a biomarker of poor prognosis, with patients experiencing a median survival of 10 months once the disease has metastasized. These patients are unresponsive to single-agent BRAF inhibition, despite its efficacy in a range ofother BRAF cancer types. Recently, phosphosubstrates of protein kinase CK2 were shown to be up-regulated in response to BRAF inhibition in BRAF thyroid cancer. We investigated the efficacy of combined BRAF/protein kinase CK2 inhibition in various BRAF colon cancer cell lines. Dual administration of CX-4945 (CK2i) with Dabrafenib (BRAFi) was effective inreducing cell viability, although not as impressively as previously reported in melanoma and thyroid cancer. Using a label-free phosphoproteomics workflow, a total of 29 phosphopeptides were up-regulated in response to BRAF inhibition. Kinase enrichment analysis of these phosphopeptides revealed that there was no enrichment of protein kinaseCK2 substrates. Rather, 58% of the enriched kinases functioned downstream of EGFR. This finding points to the clear need to control EGFR signaling in BRAF colon cancer. Kinase enrichment analysis also revealed that SRC kinase activity was enriched 7.67-fold in responseto GDC0941 (PI3Ki), providing rationale for the evaluation of dual PI3K/SRC kinase inhibitionin BRAF colon cancer cells.

History

Table of Contents

1. Introduction -- 2. Methods -- 3. Results -- 4. Discussion.

Notes

Theoretical thesis. Bibliography: pages 48-52

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

MRes, Macquarie University, Faculty of Science and Engineering, Department of Chemistry and Biomolecular Sciences

Department, Centre or School

Department of Chemistry and Biomolecular Sciences

Year of Award

2015

Principal Supervisor

Mark Molloy

Rights

Copyright Benjamin Brown 2015. Copyright disclaimer: http://www.copyright.mq.edu.au

Language

English

Extent

1 online resource (viii, 52, 6 pages) colour illustrations

Former Identifiers

mq:44578 http://hdl.handle.net/1959.14/1070440