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Title: Targeting acute resistance mechanisms inhibition in BRAFMT CRC
Author: Carson , Robbie
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Colorectal cancer (GRG) is the 3rd common cancer, and second leading cause of cancer associated mortality. Oncogenic mutations in the BRAF gene results in an altered protein structure, leading to constitutively activated MAPK signalling. Beneficial treatment strategies for this poor prognostic subgroup of GRG patients have yet to be identified. Hence this objective of this study was to identify novel treatment strategies in BRAF mutant GRG models. Our data has shown that MEK inhibition results in acute expression of pSTAT3, regulated through the c-METI JAK signalling axis. Taking a combined approach of JAKlMEK, or c-MET/MEK inhibition we have shown that these combinations results in significant increased apoptosis in BRAFMT GRG, and have potential as novel combinations. Furthermore, we are the first to show that MEK inhibition results in increased expression of the caspase 8 inhibitor c-FLlP, as a mechanism of resistance to apoptosis induction. Using a gene silencing and small-molecule inhibitor approach, we have identified that combined c-FLlP/MEK inhibition is a novel treatment strategy that may provide benefit for this subgroup of GRG patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available