Resistance to PRMT5 Targeted Therapy in Mantle Cell Lymphoma.
Academic Article
Overview
abstract
Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin's lymphoma and patients who relapse on targeted therapies have a poor prognosis. Protein arginine methyltransferase 5 (PRMT5), an enzyme essential for B-cell transformation, drives multiple oncogenic pathways and is overexpressed in MCL. Despite the anti-tumor activity of PRMT5 inhibition (PRT-382/PRT-808), drug resistance was observed in a patient derived xenograft (PDX) MCL model. Decreased survival of mice engrafted with these PRMT5 inhibitor resistant cells versus treatment-naïve cells was observed (p-value: 0.005). MCL cell lines showed variable sensitivity to PRMT5 inhibition. Using PRT-382, cell lines were classified as sensitive (n=4; IC50 20-140 nM) or primary resistant (n=4; 340-1650 nM). Prolonged culture of sensitive MCL lines with drug escalation produced PRMT5 inhibitor resistant cell lines (n=4; 200-500 nM). This resistant phenotype persisted after prolonged culture in the absence of drug and was observed with PRT-808. In the resistant PDX and cell line models, symmetric dimethylarginine reduction was achieved at the original PRMT5 inhibitor IC50 suggesting activation of alternative resistance pathways. Bulk RNA sequencing of resistant cell lines and PDX relative to sensitive or short-term treated cells, respectively, highlighted shared upregulation of multiple pathways including mTOR signaling (p-value < 10-5 and z-score >0.3 or <0.3). Single cell RNA sequencing analysis demonstrated a strong shift in global gene expression with upregulation of mTOR signaling in resistant MCL PDX samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX.
