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Investigating protein kinase CK2 inhibition in BRAF colon cancer
thesisposted on 2022-03-29, 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.