TAMI-36. CONNEXIN 43 BLOCKADE INHIBITS PROLIFERATION IN IDH1-MUTANT GLIOMA CELLS

Abstract

Abstract IDH1-mutant gliomas are characteristically sensitive to NAD+ depletion. It is known that NAD+ can move between cells through gap junctions, which provides an opportunity for treatments that prevent NAD+ sharing across tumor cells, effectively decreasing available NAD+. Previous studies have also shown the role of connexin 43 (Cx43) in mediating communication in glioma cell networks and have identified Cx43 as a potential mediator of temozolomide resistance in glioma. We hypothesized that blocking Cx43 would prevent intercellular NAD+ sharing in IDH-mutant gliomas, causing tumor cells to be more vulnerable to metabolic NAD+ depletion via nicotinamide phosphoribosyltransferase (NAMPT) inhibitors and temozolomide (TMZ) treatment. Here, we show that blockade of Cx43 with α-connexin carboxyl-terminal (ACT1) is able to inhibit growth of patient-derived IDH1-mutant tumor cells. ACT1 sensitizes cells to TMZ and inhibits growth of IDH1-mutant gliomas via an NAD-dependent mechanism. We also found that ACT1 can be used in combination with other NAD-depleting drugs, such as NAMPT inhibitors, to enhance its effect and provide a viable therapeutic window. Overall, our results suggest that ACT1 may enhance the efficacy of treatments for IDH1-mutant tumors by blocking metabolic buffering through tumor cell gap junctions.