Abstract 4695: Dual targeting of MEK and PI3K pathways can act via tumor-intrinsic mechanisms to overcome resistance and tumor-extrinsic mechanisms to modulate immunity and limit cancer cachexia

Prior studies by our group have shown that single-agent MEK inhibitors have clinical activity in cholangiocarcinoma (CC), including objective responses. Yet no relationship was found between clinical benefit, and oncogenic driver mutations such as KRAS or BRAF. Strategies to expand upon MEKi have focused on combinations with agents targeting resistance, such as the PI3K/Akt pathway. CC patients treated with MEKi also had reduced pro-inflammatory cytokines and weight gain with restoration of muscle mass. These findings are clinically significant, and led us to hypothesize that MEKi act via tumor-extrinsic mechanisms to modulate immunity and limit cancer cachexia, while overcoming tumor-intrinsic resistance. We used the colon-26 adenocarcinoma model to evaluate the effect of single and combined treatment with MEK162 (30mg/kg) and buparlisib (25mg/kg) on muscle wasting, tumor growth, and immune modulation. This murine model depends on interleukin-6 (IL-6) and recapitulates the cancer cachexia syndrome. Single agent MEK162 inhibited growth initially, but after 14 days, tumor volume was comparable between MEKi and vehicle treated mice, possibly from acquired MEK162 resistance. Despite these data, reduced serum IL-6 and splenic Gr1+CD11b+ cells were evident compared to control mice (mean = 358 pg/mL to 43 pg/mL, and 13.8% to 8.4%, respectively), while body weight from MEK162 treated mice was spared (mean = 24.0g to 20.5g in control mice). In addition, markers of muscle catabolism, including the E3 ubiquitin ligases Atrogin-1 (from 1 to 0.043 in combo) and MuRF1 (from 1 to 0.03 in combo), and the autophagy gene, Bnip3, were all reduced in tibialis anterior muscles from tumor-bearing mice treated with MEK162. Similar to our clinical data, these results suggest MEK162 modulates immune biomarkers, and acts as an anti-cachexia agent. Since cross talk between MAPK and PI3K/AKT pathways promotes resistance to monotherapy, we next investigated the effects of MEK162 combined with buparlisib in the colon-26 model. As before, single agent MEK162 had a modest growth inhibitory effect, yet rescued body weight. Consistent with in vitro studies, single agent buparlisib was cytostatic, but not as effective as MEK162 in rescuing weight loss. However, dual treatment with MEK162 + buparlisib significantly inhibited tumor growth. This combination also significantly reduced splenic MDSC (mean = 37% to 9% in control mice) and increased CD4+ and CD8+ (mean = 24% to 6%, and 7.7% to 2%, respectively) T cells. These results suggest that dual inhibition of MEK and PI3K has efficacy, while MEKi may have under-appreciated tumor-extrinsic mechanisms of activity that can be leveraged to benefit patients with advanced malignancy. This treatment combination will be evaluated in CC patients in the setting of a Phase II clinical trial. Citation Format: Jennifer Yang, Erin Talbert, Omar Elnaggar, Priyani Rajasekera, Thomas Mace, Matthew Farren, Zheng Che, Benjamin Swanson, Gregory Young, Ericka Haverick, Cynthia Timmers, Mark Bloomston, Tanios Bekaii-Saab, Denis Guttridge, Gregory Lesinski. Dual targeting of MEK and PI3K pathways can act via tumor-intrinsic mechanisms to overcome resistance and tumor-extrinsic mechanisms to modulate immunity and limit cancer cachexia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4695. doi:10.1158/1538-7445.AM2015-4695