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AACR 2022: Impact of PRMT5 Inhibition on BH3 Mimetic Sensitivity in Mantle Cell Lymphoma

By: Vanessa A. Carter, BS
Posted: Friday, April 15, 2022

A study conducted by Robert Baiocchi, MD, PhD, of Cornell University, New York, and colleagues used BH3 mimetics to identify that the protein arginine methyltransferase 5 (PRMT5) appears to be a key oncogenic driver of mantle cell lymphoma. Presented during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 1031/4), the results of this exploration support combining BH3 mimetics and PRMT5 inhibition in clinical trials as a novel treatment strategy for this malignancy.

“Selectively inhibiting PRMT5 has shown significant antitumor activity in preclinical mantle cell lymphoma models, and a phase I clinical trial with PRT543, a novel PRMT5 inhibitor, is underway,” the investigators commented.

BCL2 family proteins promote or inhibit intrinsic apoptosis at the outer mitochondrial membrane, thus this apoptotic pathway was identified as a possible target in mantle cell lymphoma. Mantle cell lymphoma cell lines CCMCL1, Z-138, UPN1, Granta 519, Mino, and Maver1 were chosen to test combination treatment ranging in sensitivity to BH3 mimetics and expression of BCL2 family proteins.

Selective inhibition of PRMT5 with the PRMT5 inhibitor PRT382 appeared to inhibit the viability of these cell lines, with an IC50 below 1 μM in eight of nine lines. BH3 mimetics A852, navitoclax (BCL inhibitors), and AMG176 (MCL1 inhibitor) were also found to have an IC50 below 1 μM in two, four, and five cell lines, respectively. Of note, cell lines Granta 519 and X-138 demonstrated a similar effect when PRT382 was combined with A852 or navitoclax.

After treatment with PRT382 or vehicle, two patient-derived xenograft models were analyzed ex vivo. Increased sensitivity of ex vivo patient-derived xenograft cells to pan BCl2, BCLXL, and MCL1 inhibition was revealed. Through BH3 profiling, these findings supported mantle cell lymphoma cell line dependence on BCL2, BCLXL, BCLw, and MCL1, as well as increased sensitivity to BCL2 family protein targeting with PRMT5 inhibition.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.


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