Lizzy Zinn – Biology

Targeting PRMT5 to Overcome Ibrutinib Resistance in Mantle Cell Lymphoma

Link to presentation: Targeting PRMT5 to Overcome Ibrutinib Resistance in Mantle Cell Lymphoma

“Introduction/Background:
Mantle cell lymphoma (MCL) is characterized by uncontrolled B-cell proliferation and survival. Although the novel targeted therapy ibrutinib has achieved an unprecedented overall response rate in MCL, nearly all patients develop drug resistance characterized by compensatory signaling through the B-cell receptor pathway. Hence the urgency in developing new treatments for ibrutinib resistant MCL patients. In lymphoma the overexpression of the epigenetic enzyme, protein arginine methyltransferase 5 (PRMT5), increases the activity of key oncogenes and silences a number of tumor suppressors leading to unrestrained B-cell proliferation and lymphomagenesis. Preliminary work in our lab and others has validated that inhibition of PRMT5 as a rationale therapeutic strategy in ibrutinib naive MCL cell lines and patient samples. Given the inhibition of PRMT5 directly modulates components of the B-cell receptor pathway responsible for ibrutinib resistance, we hypothesize that ibrutinib resistance MCL can be overcome by targeting the enzymatic activity of PRMT5.
Methods:
Western blotting was used to evaluate the protein expression of epigenetic methylation marks and downstream signaling molecules of the B-cell receptor pathway after inhibition of PRMT5 in ibrutinib resistant human MCL cell lines. Cell viability and proliferation assays were conducted in ibrutinib resistant MCL cell lines treated with PRMT5 inhibitors. Mouse models of MCL were used to establish if inhibition of PRMT5 can overcome ibrutinib resistance in vivo.
Results:
Ibrutinib resistant cell lines were sensitive to PRMT5 inhibition in vitro. In mouse models of MCL, treatment with our PRMT5 inhibitor extended survival and was more effective than ibrutinib treatment alone. We are currently interrogating the precise mechanism of PRMT5s ability to overcome ibrutinib resistance with protein and RNA level expression of the B-cell receptor pathway.
Conclusion:
Nearly all patients with MCL relapse, and those who relapse on ibrutinib have a short overall survival. This has created an urgent need for new therapies for these patients. Inhibition of PRMT5 is able to overcome ibrutinib resistance in human cell lines and preclinical mouse models of MCL. In conclusion, our research supports the continued development of PRMT5 inhibitors for MCL.”