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Resistance Mechanism Btk Review

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Submitted By jcarson112
Words 353
Pages 2
Bio 242 AM
Reading Report 1
May 29th, 2014

Paper reviewed: Woyach, J.A. et al. 2014. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. NEMJ. DOI: 10.1056/NEJMoa1400029

Summary of paper: Ibrutinib acts as an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that induces a modest amount of chronic lymphocytic leukemia (CLL) cell apoptosis stopping B-cell receptor signaling and proliferation in vitro. Ibrutinib has been shown to have clinically significant activity in patients with relapsed CLL with 71% of patients having complete or partial response and 15-20% of patients having at least a partial response. Patients treated with Ibrutinib have a 75% progression-free survival rate. This paper investigated possible resistance mechanisms to Ibrutinib associated with mutations in BTK. Mutations were determined using whole-exome sequencing of baseline samples of patients with CLL and compared to whole-exome sequences of the patients after relapse. A cysteine-to-serine mutation in BTK at the biding site was found along with three gain-of-function mutations that are downstream from the BTK binding site that lead to autonomous B-cell receptor activity.

Bias of paper:
The paper was not biased. Research was funded by Funded by the National Cancer Institute and other institutions. No conflicts of interest were included in this paper.

Conclusion supported? Mutations of BTK binding site and B-cell receptor pathways in this study suggest that BTK is a critical target for the mechanism action of Ibrutinib. More knowledge of down stream mediators of Ibrutinib resistance can help to develop prevention and treatment of BTK inhibitor resistant CLL. However, more studies will need to be done to illustrate the statistical significance of this paper as this study only looked at a sample of 6 patients with acquired resistance to Ibrutinib therapy.

Relevance/Importance of research: Understanding the overall effect of BTK inhibitors on treatment of patients with CLL, and the potential to cause resistance to valuable treatment avenues is very significant. The American Cancer Society estimates that there will be approximately 15,720 new cases and 4,600 deaths in the US in 2014 from CLL.

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