Increased expression of the tight junction protein TJP1/ZO-1 is associated with upregulation of TAZ-TEAD activity and an adult tissue stem cell signature in carfilzomib-resistant multiple myeloma cells and high-risk multiple myeloma patients

Abstract

Tight junction protein 1 (TJP1) has recently been proposed as a biomarker to identify multiple myeloma (MM) patients most likely to respond to bortezomiband carfilzomib-based proteasome inhibitor regimens. Herein we report increased expression of TJP1 during the adaptive response mediating carfilzomib resistance in the LP-1/Cfz MM cell line. Moreover, increased TJP1 expression delineated a subset of relapsed/refractory MM patients on bortezomib-based therapy sharing an LP-1/Cfzlike phenotype characterized by activation of interacting transcriptional effectors of the Hippo signaling cascade (TAZ and TEAD1) and an adult tissue stem cell signature. siRNA-mediated knockdown of TJP1 or TAZ/TEAD1 partially sensitized LP-1/Cfz cells to carfilzomib. Connectivity Map analysis identified translation inhibitors as candidate therapeutic agents targeting this molecular phenotype. We confirmed this prediction by showing that homoharringtonine (omacetaxine mepesuccinate) — the first translation inhibitor to be approved by the U.S. Food and Drug Administration — displayed potent cytotoxic activity on LP-1/Cfz cells. Homoharringtonine treatment reduced the levels of TAZ and TEAD1 as well as the MM-protective proteins Nrf2 and MCL1. Thus, our data suggest the importance of further studies evaluating translation inhibitors in relapsed/refractory MM. On the other hand, use of TJP1 as a MM biomarker for proteasome inhibitor sensitivity requires careful consideration.