Abstract C267: Sequential combination of the novel allosteric MEK1/2 inhibitor BAY 86-9766 (RDEA119) with the mTOR inhibitor rapamycin decelerates relapse of pancreatic tumors.

Abstract

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating, deadly malignancy in the western world with a 5-year overall survival rate of less than 4% due to (1) difficult early diagnosis, (2) early metastatic spread as well as (3) high intrinsic resistance to known chemotherapies and ionizing radiation. Therefore, novel treatment strategies and improved mouse models for better prediction of clinical efficacy of new chemotherapeutic agents are urgently needed. In this study we investigated the effect of a sequential therapy strategy in a genetically engineered mouse model for PDAC combining the novel MEK1/2 inhibitor BAY 86-9766 with the mTOR inhibitor rapamycin. Experimental Procedure: Using a Cre/loxP approach we generated mice with pancreas-specific activation of oncogenic KRAS and concurrent deletion of p53 (Ptf1a+/Cre, Kras+/LSL-G12D, p53loxP/loxP; CKP) to mimic human PDAC on a molecular and morphological level. These mice typically develop lethal invasive PDAC within 8 weeks of age. Non-invasive magnetic resonance imaging (MRI) was used to track tumor progression during therapy. Primary tumor cells isolated from vehicle and BAY 86-9766 treated animals were used for molecular and functional assays to identify possible resistance mechanisms for the development of sequential therapy strategies. Results: Treatment of CKP mice with BAY 86-9766 alone resulted in an effective tumor regression already after 1 week of therapy. This massive tumor shrinkage was caused by a strong apoptosis induction specifically in tumor cells starting after 4h of treatment accompanied with caspase 3/7 activation and PARP cleavage from ex vivo samples. Moreover, BAY 86-9766 treatment resulted in a phosphorylation decrease of its target ERK1/2. Despite the potent apoptosis induction some remaining tumor cells are escaping from this induced cell death, causing the tumor relapse seen in CKP mice with continuing therapy. To investigate the underlying resistance mechanism we established long-term treated resistant cell lines. Those cells exhibit a phosphorylation upregulation of both AKT residues (thr308 and ser473) as well as of S6, a direct target of mTOR, suggesting full activation of the PI3K/AKT/mTOR signaling cascade to overcome resistance. Therefore, we started a sequential therapy strategy of BAY 86-9766 with the mTOR inhibitor rapamycin. Mice, first treated 1-2 weeks with BAY 86-9766 and afterwards with rapamycin until death, showed a significant overall survival benefit compared to their BAY 86-9766 and vehicle treated counterparts. Furthermore, we could demonstrate by MRI, that rapamycin decelerates the tumor relapse in responder mice. Conclusion: These preclinical data provide in vivo evidence, that the development of sequential therapy strategies for PDAC is of paramount importance to overcome resistance and to enhance the efficacy of targeted therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C267. Citation Format: Nicole Teichmann, Marija Trajkovic-Arsic, Arne Scholz, Roland M. Schmid, Rickmer Braren, Jens T. Siveke. Sequential combination of the novel allosteric MEK1/2 inhibitor BAY 86-9766 (RDEA119) with the mTOR inhibitor rapamycin decelerates relapse of pancreatic tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C267.