Abstract CN05-03: Cooperation between a rexinoid and EGFR-TKI for lung cancer prevention via Cyclin D1 destabilization
Authors: Dragnev Konstantin H. , Memoli Vincent , Freemantle Sarah J. , Waxman Samuel , Dmitrovsky Ethan 
Published: October 2015

We previously reported that both nuclear retinoic acid receptor (RAR, retinoid) and retinoid X receptor (RXR, rexinoid) agonists can trigger proteasomal degradation of cyclins. This confers check point arrest and repair of carcinogenic DNA damage in bronchial epithelial cells. Mechanisms responsible for this induced degradation were discovered. These included ubiquitin-dependent as well as ISG15-dependent programs that independently destabilized expression of cyclin D1 and other G1 cyclin proteins. The critical receptor that confers this cyclin destabilization was RARβ. Yet, silencing of RARβ; and specifically of the previously unrecognized isoform that we cloned and designated as RARβ1 likely accounts for clinical resistance to classical retinoids (like 13-cis-retinoic acid and all-trans-retinoic acid) in lung carcinogenesis. We sought to learn whether RXR/RAR heterodimer complex activation with a rexinoid was able to trigger cyclin destabilization. This was found to be the case in in vitro studies. This finding implied that the same pathway would be engaged in the in vivo setting. To establish if this occurs, we engineered transgenic mice independently with human surfactant C-driven wild-type cyclin E or a proteasome-degradation resistant cyclin E species. This mouse model was developed because human pre-malignant and malignant lung lesions frequently deregulate cyclin expression. Intriguingly, these mice recapitulated many features of lung carcinogenesis found in patients. Neoplastic changes were enhanced by transgenic expression of the degradation-resistant cyclin E species. We built on this finding by showing that a rexinoid and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) each chemoprevented lung cancers in vinyl carbamate-induced lung tumors within strain A/J mice. Notably, the rexinoid was more potent that the EGFR-TKI in conferring this chemoprevention. Both agents also reduced cyclin expression, but did so through distinct mechanisms. We sought to learn if a rexinoid (bexarotene) cooperated with an EGFR-TKI (erlotinib) in exerting anti-tumorigenic effects in lung cancer. Cooperation between these agents was found in both murine and human lung cancer cells and even in those cells that exhibited KRAS/p53 mutations. Over the past decade, we translated this work into the cancer clinic through a series of five clinical trials that moved this work through successive phase 0, phase I, and phase II trials of lung and aerodigestive tract cancers. In window of opportunity trials, pharmacodynamic responses (cyclin repression and induced necrosis and inflammatory responses) were seen when intratumoral levels of these drugs were comparable to those necessary to trigger in vitro effects. A phase II trial in heavily pre-treated stage IV non-small cell lung cancer (NSCLC) cases was performed. EGFR and cyclin expression profiles as well as KRAS mutations were searched for in these NSCLC cases. Findings revealed substantial cyclin repression and reduction of lung cancer growth by combined therapy with a rexinoid (bexarotene) and EGFR-TKI (erlotinib). Cyclins were repressed while necrosis and inflammation were induced in post-treatment versus pre-treatment lung tumor biopsies obtained in this window of opportunity trial. Objective anti-tumor responses occurred whether or not KRAS or activating EGFR mutations were detected. This refractory NSCLC trial had 3 major clinical responses (2 had KRAS or EGFR mutations) with prolonged survival (583, 665, and 1460+ days, respectively). Median survival was 22 weeks (16 weeks for controls). Hypertriglyceridemia or rash significantly increased median overall survival to 24 weeks. Thus, this combination regimen revealed substantial clinical anti-tumor activity against NSCLCs. Taken together, these findings indicate that cooperation between a rexinoid and EGFR-TKI can chemoprevent and treat lung cancers by causing cyclin destabilization. These agents are also useful tools to identify other antineoplastics that repress lung cancers by destabilizing cyclin expression or by inhibiting their associated kinases. Evidence for this will be presented in this session.

Citation Format: Konstantin H. Dragnev, Vincent Memoli, Sarah J. Freemantle, Samuel Waxman, Ethan Dmitrovsky. Cooperation between a rexinoid and EGFR-TKI for lung cancer prevention via Cyclin D1 destabilization. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN05-03.