*Article* **Differential Response of Lung Cancer Cells, with Various Driver Mutations, to Plant Polyphenol Resveratrol and Vitamin D Active Metabolite PRI-2191**

**Ewa Maj 1,\* , Beata Maj <sup>1</sup> , Klaudia Bobak <sup>1</sup> , Michalina Gos <sup>1</sup> , Michał Chody ´nski <sup>2</sup> , Andrzej Kutner <sup>3</sup> and Joanna Wietrzyk <sup>1</sup>**


**Abstract:** Plant polyphenols and vitamins D exhibit chemopreventive and therapeutic anticancer effects. We first evaluated the biological effects of the plant polyphenol resveratrol (RESV) and vitamin D active metabolite PRI-2191 on lung cancer cells having different genetic backgrounds. RESV and PRI-2191 showed divergent responses depending on the genetic profile of cells. Antiproliferative activity of PRI-2191 was noticeable in EGFRmut cells, while RESV showed the highest antiproliferative and caspase-3-inducing activity in KRASmut cells. RESV upregulated p53 expression in wtp53 cells, while downregulated it in mutp53 cells with simultaneous upregulation of p21 expression in both cases. The effect of PRI-2191 on the induction of CYP24A1 expression was enhanced by RESV in two KRASmut cell lines. The effect of RESV combined with PRI-2191 on cytokine production was pronounced and modulated. RESV cooperated with PRI-2191 in regulating the expression of IL-8 in EGFRmut cells, while OPN in KRASmut cells and PD-L1 in both cell subtypes. We hypothesize that the differences in response to RESV and PRI-2191 between EGFRmut and KRASmut cell lines result from the differences in epigenetic modifications since both cell subtypes are associated with the divergent smoking history that can induce epigenetic alterations.

**Keywords:** anticancer activity; lung cancer; resveratrol; PRI-2191; vitamin D
