# Cancer cell death induced by the NAD antimetabolite Vacor discloses the antitumor potential of SARM1

## TL;DR

The study shows that activating SARM1, a NAD-depleting enzyme, can kill cancer cells and suggests a new approach for cancer treatment.

## Contribution

The study reveals that SARM1 activation is a novel anticancer therapeutic strategy.

## Key findings

- Vacor-induced NAD depletion and cell death are not affected by changes in NMNAT2 levels.
- SARM1 expression alone is sufficient to induce sensitivity to Vacor in cancer cells.
- Cancer cells upregulate NMNAT2 in response to SARM1 expression.

## Abstract

In a previous study, we showed that the NAD antimetabolite Vacor is metabolized by two enzymes implicated in the NAD salvage pathway—to Vacor mononucleotide (VMN) by nicotinamide phosphoribosyltransferase (NAMPT) and, in turn, to Vacor adenine dinucleotide (VAD) by nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2)—leading to NAD depletion and antitumor activity. Recent findings in neurons show that VMN activates SARM1, a NAD glycohydrolase, triggering NAD depletion and degeneration. In this study, we report that altering NMNAT2 levels did not affect Vacor‐induced NAD depletion or cell death. In contrast, SARM1 expression alone was sufficient to induce Vacor sensitivity. Further, we report that cancer cells sense the abnormal expression of SARM1 and readily induce the expression of NMNAT2. Overall, the data underscore the antitumor potential of pharmacological approaches aimed at activating SARM1.

Vacor, a compound converted into the toxic metabolite Vacor adenine dinucleotide (VAD) by the nicotinamide salvage pathway enzymes NAMPT and NMNAT2, exhibits antitumor activity by inducing rapid and complete NAD depletion. We report that Vacor toxicity is limited to cell lines expressing high levels of SARM1, a NAD glycohydrolase. These SARM1‐positive cell lines also show elevated expression of NMNAT2. Our data reveal SARM1 activation as a novel anticancer therapeutic strategy.