Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Abstract

Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

NAD+ Metabolism and Regulation: Lessons From Yeast

“…Supporting this, the combination of PARP inhibitors and Nampt inhibitors was shown to induce synthetic lethality in breast cancer cells [140]. The roles of Nampt and NAD + metabolism in metabolic diseases such as cancers and diabetes have been extensively discussed in several recent reviews [5,6,134,138,[141][142][143]. Here we discuss the roles of NAD + , NAD + biosynthesis enzymes Nmnats and NAD + -dependent sirtuins in select diseases of the nervous system.…”

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

“…Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD salvage pathway, is the greatest contributor in generating NAD in mammals [1,2]. Overexpression of NAMPT has been implicated in several cancers [3][4][5]. On the other hand, nicotinate phosphoribosyltransferase (NAPRT) also produces NAD through the nicotinic acid pathway [1,6].…”

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma

“…Cellular NAD can be produced through several redundant synthesis pathways, some of which include enzymes that are over-expressed or silenced in certain cancers 3,[9][10][11][12][13][14][15][16] . The salvage pathway represents one such pathway of key importance in cancer, functioning to recycle nicotinamide (NAM), the product of NAD + -consuming enzymes, back into NAD +17 .…”

“…In the salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT) acts as the rate-limiting enzyme and produces nicotinamide mononucleotide (NMN), an NAD precursor 3,[15][16][17] . In certain cancers, NAMPT expression has been shown to promote carcinogenesis and is associated with worse prognosis 3,9,16 . Preclinically, pharmacological inhibitors of NAMPT have been shown to deplete NAD, resulting in loss of cell viability in a variety of cancer types [6][7][8]10,[18][19][20][21] .…”

“…In addition, recent evidence has emerged demonstrating that certain tumor types may be more sensitive to inhibition of NAMPT due to differential vulnerabilities in NAD-related processes 9 . Ewing sarcoma (EWS), a pediatric bone and soft tissue cancer, represents one such malignancy as recent studies have revealed the presence of intrinsic defects in DNA damage repair and metabolic reprogramming [35][36][37][38][39] .…”