Pentadecanoic Acid (C15:0) at Naturally Occurring Circulating Concentrations Has Selective Anticancer Activities Including Targeting B-Cell Lymphomas with CCND3 Oncogenic Alterations

<b>Background/Objectives:</b> While pentadecanoic acid (C15:0), present in whole dairy fat, has broad anticancer activities at high concentrations, the presence of C15:0 anticancer activities at naturally occurring circulating concentrations is less clear. <b>Methods:</b> Using an independent service to run the Eurofins OncoPanel^TM Cell Proliferation Assay, C15:0 was screened for dose-dependent antiproliferation activities against 94 human cancer cell lines at 10 concentrations ranging between 1.5 nM and 50 µM. Oncogenic alterations were compared between cell lines in which C15:0 did or did not have antiproliferation activities. <b>Results:</b> C15:0 had dose-dependent antiproliferation activities (EC50 ≤ 50 µM) among 13 (13.8%) cancer cell lines, most of which were non-Hodgkin B-cell lymphomas (n = 8, 61.5% of C15:0-responsive cell lines), but also included liver (n = 2, 15.4%), breast (n = 2, 15.4%), and lung (n = 1, 7.7%) cancers. C15:0 had robust antiproliferation activities (EC₅₀, IC₅₀ and GI₅₀ ≤ 50 µM) in four cell lines, all of which were non-Hodgkin B-cell lymphomas. When comparing oncogenic alterations among C15:0-responsive versus non-responsive cancer cell lines (n = 79 with available data on DepMap), 4 of 18 (22%) C15:0-responsive cell lines had a CCND3 mutation compared to 1 of 61 (1.6%) non-responsive cell lines (<i>p</i> = 0.007, OR = 17.1, 95% CI 1.8-165). Three of four (75%) of the most C15:0-responsive B-cell lymphomas had the CCND3 alteration (<i>p</i> = 0.0004, OR = 180, 95% CI 8.9-3632). <b>Conclusions:</b> C15:0 has selective dose-dependent anticancer activities at naturally occurring concentrations. The potential use of C15:0 against cancers with CCND3 genetic alterations warrants further exploration. Further, there is a need to better understand the potential role of nutritional C15:0 deficiencies and CCND3 alterations on the observed rise in certain types of cancers, especially among young adults.