Abstract LB-170: A novel, nontoxic RXR agonist, UAB30, targets Fanconi anemia DNA repair pathway to act as potent cancer chemopreventive agent

Abstract

Abstract UAB30, a synthetic analog of 9-cis-RA is a potent retinoid X receptors (RXR) agonist. It was found to have significantly low retinoic acid receptor (RAR)-binding activity. This unique property of UAB30 is responsible for its low lipid toxicity. Thus, it does not cause elevation in serum triglycerides both in humans and in experimental animals. These properties with favorable pharmacokinetics make it a suitable candidate for chronic use as chemopreventive agent. Here, we show that UAB30 is highly effective in inhibiting UVB-induced pathogenesis of skin cancers in Ptch1+/-/SKH-1 hairless mice. Similar to humans, this unique genetically engineered murine model develops both basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin following chronic UVB irradiation. Compared to controls, the UAB30-treated group showed a 48% reduction in tumor number and a 78% reduction in tumor volume. The number of papillomas, BCCs, and SCCs were reduced by 33%, 74%, and 76%, respectively. UAB30 also diminished UVB-induced skin inflammation, hyperplasia, and enhanced differentiation of suprabasal epidermal cells. The expression of cyclins A, D1, D2, and D3, and cdc25A were decreased in UAB30 treated SCCs, while pro-apoptotic proteins, Bax and cleaved caspase 3 were increased. UAB30 when topically applied 30 min after each UVB irradiation for 30 weeks, it showed significant reduction in cancer development. A 57% reduction in tumor number and 72% reduction in tumor volume were observed. BCCs and SCCs were reduced by 55% and 60%, respectively. We also demonstrate that UAB30 acts by a unique molecular mechanism. Induction of lethal DNA double strand breaks (DSBs) characterized by the presence of p-γH2AX was observed following UAB30 treatment. These effects were more prominent in cancer cells than normal keratinocytes. Induction of DSBs was associated with the activation of DNA damage response (DDR) signaling leading to increased phosphorylation of ATM, Rad50, and Chk2. These effects paralleled with the reduction in cell cycle proteins and cell cycle arrest in G2/M phase followed by apoptosis of arrested cells. UAB30-induced DSBs and DDR were not dependent on ROS as we did not observe significant induction of ROS in UAB30-treated cells and did not notice any protective effect of N-acetyl cysteine. These effects were similar to DDR and changes in proliferation/apoptosis response observed following treatment with cisplatin which is known inducer of DSBs. Moreover, other RXR agonists were significantly less potent in inducing DSBs and DDR responses. The underlying mechanism for the accumulation of DSBs was the diminished ability of cancer cells to repair these DNA lesions. Reduction in FANCD2 and FANCC, the Fanconi anemia core complex proteins which are known to be involved in DSBs repair appear to be the cause of extensive DNA damage associated tumor cell death. Citation Format: Sandeep C. Chaudhary, Craig A. Elmets, Mohammad Athar. A novel, nontoxic RXR agonist, UAB30, targets Fanconi anemia DNA repair pathway to act as potent cancer chemopreventive agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-170. doi:10.1158/1538-7445.AM2017-LB-170