Combination Of An Erk1/2 Inhibitor (Ly3214996) With Vegfr-2 Inhibitor Enhances Anti-Tumor Activity In Kras Mutant Non-Small Cell Lung Cancer

Lung cancer is a leading cause of cancer death worldwide. ERK1/2, a key downstream effector of RAS mutations, is involved in the signaling network which drives cell proliferation, survival, metastasis and cancer resistance to drug treatment. KRAS mutation driven MAPK activation is present in ~ 30% of lung cancer patients. Non-small cell lung cancer (NSCLC) patients with KRAS mutation have poor prognosis and represents an unmet medical need. LY3214996, an ERK1/2 inhibitor which is in a phase I clinical trial, has anti-tumor activities in RAS mutant tumor cells in vitro and in vivo (http://cancerres.aacrjournals.org/content/77/13_Supplement/4973). Ramucirumab, a fully-human monoclonal antibody to human VEGFR-2 was approved as an anti-angiogenic treatment for several cancer indications including second-line NSCLC. Combination strategies in cancer including targeting both tumor cells and the surrounding stroma including endothelial cells have been shown to be effective in various tumor subtypes. In this study, the combination effect of LY3214996 with VEGFR-2 inhibitor DC101 (a monoclonal antibody specific for murine VEGFR-2 and a surrogate for ramucirumab) were evaluated in KRAS mutant NSCLC models, including NCI-H2122 (G-12C), A549 (G-12S) and NCI-H441 (G-12V). LY3214996 treatment alone resulted in 41%, 91% and 101% tumor growth inhibition in H2122, A549 and H441 xenograft tumors, respectively. DC101 treatment alone resulted in 64%, 75% and 102% tumor growth inhibition in H2122, A549 and H441, respectively. The combination of LY3214996 with DC101 led to better tumor growth inhibition 83%, 115% (i.e. 15% regression) and 146% (i.e. 46% regression) for H2122, A549 and H441, respectively when compared with single agent treatment. The molecular mechanism was further investigated in H2122 tumor xenograft tumors in terms of MAPK signaling, MAPK gene signatures, tumor vascularization, cell proliferation and apoptosis. LY3214996 together with DC101 led to greater reduction in tumor blood vessels density compared to DC101 alone. Similarly, the analysis of multiple cell cycle markers (including pRb, pH3 and Ki67) indicated that the combination treatment resulted in greater inhibited of cell proliferation compared to single agent. Moreover, the combination effect of LY3214996 with ramucirumab was also investigated via tumor cell driven cord formation assays in vitro ; and the data indicated that the combination enhanced the inhibition of cord formation when compared to single agent. Overall, combined inhibition of ERK1/2 and VEGFR-2 enhanced both anti-angiogenesis and antitumor effects. Taken together, these data support further clinical development of the combination of an ERK1/2 inhibitor, LY3214996 with ramucirumab in the treatment of KRAS mutant NSCLC. Citation Format: Wenjuan Wu, Shripad V. Bhagwat, Bonita D. Jones, Michelle L. Swearingen, Beverly L. Falcon, William T. McMillen, Sajan Joseph, Sean Buchanan, Sheng-Bin Peng, Christoph Reinhard, Ramon V. Tiu. Combination of an ERK1/2 inhibitor (LY3214996) with VEGFR-2 inhibitor enhances anti-tumor activity in KRAS mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-185.