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Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma (Mouse NAMPT targeted therapy)

ABSTRACT:

NAMPT plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells was associated with down-regulation of genes relevant to QPRT-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also found that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but NMRK1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations was synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

Mouse NAMPT targeted therapy is reported in the current study MTBLS7252.

Cell NAMPTi treatment is reported in MTBLS7251.

Mouse NAD targeted time-course is reported in MTBLS7253.

INSTRUMENT(S): Capillary electrophoresis MS - positive, Capillary electrophoresis MS - negative

SUBMITTER: Rintaro Saito Nobuhiro TANUMA

PROVIDER: MTBLS7252 | MetaboLights | 2023-10-10

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS7252	Other
	FILES	Other
	a_MTBLS7252_CE-MS_negative__metabolite_profiling.txt	Txt
	a_MTBLS7252_CE-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma (Cell NAMPTi treatment)

Project description:NAMPT plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells was associated with down-regulation of genes relevant to QPRT-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also found that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but NMRK1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations was synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma. Cell NAMPTi treatment is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7251' rel='noopener noreferrer' target='_blank'>MTBLS7251</a>.Mouse NAMPT targeted therapy is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7252' rel='noopener noreferrer' target='_blank'>MTBLS7252</a>.Mouse NAD targeted time-course is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7253' rel='noopener noreferrer' target='_blank'>MTBLS7253</a>.

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Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma (Mouse NAD targeted time-course)

Project description:NAMPT plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells was associated with down-regulation of genes relevant to QPRT-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also found that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but NMRK1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations was synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma. Mouse NAD targeted time-course is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7253' rel='noopener noreferrer' target='_blank'>MTBLS7253</a>.Cell NAMPTi treatment is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7251' rel='noopener noreferrer' target='_blank'>MTBLS7251</a>.Mouse NAMPT targeted therapy is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7252' rel='noopener noreferrer' target='_blank'>MTBLS7252</a>.

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