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Nicotinic Acid Restriction Enhances the Therapeutic Benefit of NAMPT Inhibition in Small-Cell Lung Cancer Models
Kyoji Tsurumi1,2,3, Miyuki Nomura1, Mai Ouchi1
1Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.
Abstract:
Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. We previously showed that nicotinic acid riboside (NAR) sustains NAD biosynthesis in vivo and compensates for NAMPT inhibition in SCLC models. Here, we evaluated combining NAMPT inhibition with dietary nicotinic acid (NA) restriction to suppress NAR-dependent NAD biosynthesis. This combination showed enhanced antitumor activity consistent with synthetic lethality in SCLC CDX models and showed robust efficacy in PDX models, including those derived from chemotherapy-refractory tumors. In most CDX models examined, combination therapy showed greater antitumor activity than standard chemotherapy with cisplatin and etoposide. Although we did observe transient leukopenia, the treatment was otherwise better tolerated than chemotherapy, with less impact on body weight and platelet counts. These findings support NAD metabolism-targeted therapy as a promising strategy to treat SCLC.
Insights
Combining NAMPT inhibition with dietary nicotinic acid restriction shows enhanced antitumor activity in small-cell lung cancer (SCLC) models. This novel therapeutic strategy offers a promising approach for treating SCLC, even in chemotherapy-refractory cases.
Area of Science:
- Oncology
- Metabolic Pathways
- Cancer Therapeutics
Background:
- Small-cell lung cancer (SCLC) is an aggressive cancer with limited treatment options.
- Nicotinic acid riboside (NAR) supports NAD biosynthesis and can counteract NAMPT inhibition in SCLC.
- Targeting NAD metabolism presents a potential therapeutic avenue for SCLC.
Purpose of the Study:
- To investigate the combined efficacy of NAMPT inhibition and dietary nicotinic acid (NA) restriction in SCLC.
- To evaluate if this combination induces synthetic lethality by suppressing NAR-dependent NAD biosynthesis.
- To compare the antitumor activity and tolerability of this combination therapy against standard chemotherapy.
Main Methods:
- Utilized SCLC cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models.
- Administered combination therapy involving NAMPT inhibition and dietary NA restriction.
- Assessed antitumor activity, efficacy in chemotherapy-refractory models, and treatment tolerability (body weight, platelet counts, leukopenia).
Main Results:
- The combination therapy demonstrated enhanced antitumor activity in SCLC CDX models, consistent with synthetic lethality.
- Robust efficacy was observed in PDX models, including those resistant to chemotherapy.
- Combination therapy showed superior antitumor activity compared to cisplatin and etoposide in most CDX models and was better tolerated, with less impact on body weight and platelets.
Conclusions:
- Targeting NAD metabolism through combined NAMPT inhibition and dietary NA restriction is a promising strategy for SCLC treatment.
- This approach shows significant potential, particularly for chemotherapy-refractory SCLC.
- The combination therapy offers a potentially more tolerable alternative to conventional chemotherapy.
