Abstract LB-083: Combination of an ERK1/2 inhibitor (LY3214996) with pan-RAF inhibitor enhances anti-tumor activity in KRAS mutant colorectal cancer (CRC) and non-small cell lung cancer (NSCLC)
Authors: Wu Wenjuan , Bhagwat Shripad , Kindler Lisa , McMillen William , Joseph Sajan , Buchanan Sean , Reinhard Christoph , Tiu Ramon V. , Peng Sheng-Bin 
Published: August 2019

Abstract
Cancer patients with KRAS mutations have poor prognosis and represent an unmet medical need. Mutant KRAS driven MAPK activation is present in ~ 40% and ~ 30% of CRC and NSCLC patients, respectively. ERK1/2, a key downstream effector of KRAS mutations, is involved in the critical signaling network to drives cell proliferation, survival, metastasis and drug resistance. LY3214996, an ERK1/2 inhibitor which is in Phase I clinical trial (NCT02857270), has potent anti-tumor activities in KRAS mutant tumor cells in vitro and in vivo. However, some KRAS mutant cancer cells were less sensitive to LY3214996 single agent, suggesting that combination therapy is needed to maximize the benefit from ERK1/2 inhibition. The combined inhibition of RAS/RAF/MEK/ERK pathway components (such as the inhibition of both BRAF and MEK) has shown the promising anti-cancer activity in melanoma. Based on interaction between activated RAS with RAF which is responsible for cancer progression and resistance in KRAS mutant cancers, we hypothesized that inhibiting both ERK and RAF may augment efficacy of the single agents and delay the resistance. Therefore in this study we have investigated the combination effect of LY3214996 with a pan-RAF inhibitor LY3009120 in KRAS mutant CRC and NSCLC in vitro and in vivo. The combination of LY3214996 and LY3009120 showed synergistic or additive inhibition of cell proliferation in all KRAS mutant CRC (n=8) and NSCLC (n=8) cell lines tested. The LY3214996 and LY3009120 combination significantly decreased the phosphorylation levels of ERK, Rb, S6 and H3, and induced more complete cell death in NCI-H2122 (G-12C), A549 (G-12S), NCI-H441 (G-12V), HCT-116 (G-13D) and in LY3009120-resistant HCT-116 cells compared with either single agent. Subsequent combination efficacy was evaluated in the HCT-116 xenograft model. LY3214996 alone, LY3009120 alone and the combination of LY3214996 and LY3009120 resulted in 52%, 68% and 94% tumor growth inhibition, respectively; and the combination significantly augmented the efficacy (p &lt;0.001). Furthermore the combination efficacy of LY3214996 with a different pan-RAF inhibitor (LSN3074753, a surrogate and an analogue of LY3009120) was also assessed in the H441 NSCLC orthotopic model, and the combination increased the inhibition of both primary tumor growth and spontaneous metastasis (including lymph node metastasis and chest wall metastasis) when compared with the respective single agent activity. Overall, the combined inhibition of ERK1/2 and RAF was tolerated and enhanced antitumor efficacy in KRAS mutant CRC and NSCLC preclinical models. These data support the feasibility of combining ERK inhibitor LY3214996 with a pan-RAF inhibitor as a promising strategy for the treatment of KRAS mutant CRC and NSCLC.
Citation Format: Wenjuan Wu, Shripad Bhagwat, Lisa Kindler, William McMillen, Sajan Joseph, Sean Buchanan, Christoph Reinhard, Ramon V. Tiu, Sheng-Bin Peng. Combination of an ERK1/2 inhibitor (LY3214996) with pan-RAF inhibitor enhances anti-tumor activity in KRAS mutant colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-083.