PMID- 36077374
OWN - NLM
STAT- MEDLINE
DCOM- 20220912
LR  - 20220913
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 17
DP  - 2022 Sep 1
TI  - NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and 
      Prospective Therapeutic Targets.
LID - 10.3390/ijms23179985 [doi]
LID - 9985
AB  - Malignant melanoma represents the most fatal skin cancer due to its aggressive 
      behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors 
      and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved 
      patient survival over the last decade. However, many patients either display 
      primary (i.e., innate) or develop secondary (i.e., acquired) resistance to 
      systemic treatments. Therapeutic resistance relies on the rewiring of multiple 
      processes, including cancer metabolism, epigenetics, gene expression, and 
      interactions with the tumor microenvironment that are only partially understood. 
      Therefore, reliable biomarkers of resistance or response, capable of facilitating 
      the choice of the best treatment option for each patient, are currently missing. 
      Recently, activation of nicotinamide adenine dinucleotide (NAD) metabolism and, 
      in particular, of its rate-limiting enzyme nicotinamide phosphoribosyltransferase 
      (NAMPT) have been identified as key drivers of targeted therapy resistance and 
      melanoma progression. Another major player in this context is the mammalian 
      target of rapamycin (mTOR) pathway, which plays key roles in the regulation of 
      melanoma cell anabolic functions and energy metabolism at the switch between 
      sensitivity and resistance to targeted therapy. In this review, we summarize 
      known resistance mechanisms to ICIs and targeted therapy, focusing on metabolic 
      adaptation as one main mechanism of drug resistance. In particular, we highlight 
      the roles of NAD/NAMPT and mTOR signaling axes in this context and overview data 
      in support of their inhibition as a promising strategy to overcome treatment 
      resistance.
FAU - Indini, Alice
AU  - Indini A
AUID- ORCID: 0000-0001-8686-4106
AD  - Division of Medical Oncology, Department of Medicine and Surgery, Ospedale di 
      Circolo e Fondazione Macchi, ASST dei Sette Laghi, 21100 Varese, Italy.
FAU - Fiorilla, Irene
AU  - Fiorilla I
AD  - Department of Science and Technological Innovation, University of Eastern 
      Piedmont, 15121 Alessandria, Italy.
FAU - Ponzone, Luca
AU  - Ponzone L
AUID- ORCID: 0000-0002-6145-129X
AD  - Department of Molecular Biotechnology and Health Sciences, Molecular 
      Biotechnology Center "Guido Tarone", University of Turin, 10126 Torino, Italy.
FAU - Calautti, Enzo
AU  - Calautti E
AUID- ORCID: 0000-0002-4439-9709
AD  - Department of Molecular Biotechnology and Health Sciences, Molecular 
      Biotechnology Center "Guido Tarone", University of Turin, 10126 Torino, Italy.
FAU - Audrito, Valentina
AU  - Audrito V
AUID- ORCID: 0000-0002-5660-4175
AD  - Department of Science and Technological Innovation, University of Eastern 
      Piedmont, 15121 Alessandria, Italy.
LA  - eng
GR  - MFAG 26004/Italian Association for Cancer Research/
PT  - Journal Article
PT  - Review
DEP - 20220901
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cytokines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0U46U6E8UK (NAD)
RN  - EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cytokines/metabolism
MH  - Drug Resistance
MH  - Humans
MH  - *Melanoma/metabolism
MH  - NAD/metabolism
MH  - Nicotinamide Phosphoribosyltransferase/metabolism
MH  - Protein Kinase Inhibitors
MH  - *Skin Neoplasms/drug therapy
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Microenvironment
PMC - PMC9456568
OTO - NOTNLM
OT  - NAMPT
OT  - cancer therapy
OT  - drug resistance
OT  - mTOR
OT  - melanoma
OT  - metabolic reprogramming
OT  - signaling
COIS- The authors declare no conflict of interest.
EDAT- 2022/09/10 06:00
MHDA- 2022/09/14 06:00
PMCR- 2022/09/01
CRDT- 2022/09/09 01:08
PHST- 2022/08/02 00:00 [received]
PHST- 2022/08/29 00:00 [revised]
PHST- 2022/08/30 00:00 [accepted]
PHST- 2022/09/09 01:08 [entrez]
PHST- 2022/09/10 06:00 [pubmed]
PHST- 2022/09/14 06:00 [medline]
PHST- 2022/09/01 00:00 [pmc-release]
AID - ijms23179985 [pii]
AID - ijms-23-09985 [pii]
AID - 10.3390/ijms23179985 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Sep 1;23(17):9985. doi: 10.3390/ijms23179985.