Abstract 1307: Inhibition of ERK by LY3214996 augments nab-paclitaxel and gemcitabine combination chemotherapy efficacy in preclinical models of pancreatic cancer
Authors: Bhagwat Shripad V. , Wu Wenjuan , Zhao Baohui , Shen Weihua , Kindler Lisa , Stephens Jennifer , Manro Jason , McMillen William , Joseph Sajan , Peng Sheng-Bin , Tiu Ramon V. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the third most frequent cause of cancer deaths in the US and is expected to be the second deadliest cancer by 2030. The 5-year survival rate in PDAC patients is only 6% and the poor prognosis is attributed to several factors including late-stage diagnosis, aggressive disease progression and high resistance to conventional therapies. Therefore, there is an urgent need for more effective systemic treatment strategies in PDAC patients. Nab-paclitaxel (Nab-pac) combined with gemcitabine (Gem) or FOLFIRINOX combination chemotherapy regimen are approved as standard of care treatment for frontline metastatic PDAC. Due to limited clinical efficacy of current cytotoxic chemotherapy regimens for PDAC patients, novel approaches are needed to further improve patient survival outcomes. In PDAC, activating mutations in KRAS occur at a frequency of ~90% rendering this a potential therapeutic target of interest. Developing drugs that directly target mutant KRAS protein remains challenging and alternative strategies focus on inhibition of downstream targets of the RAS-MAPK cascade. The addition of ERK inhibitor LY3214996 to the chemotherapy regimen (Nab-pac+Gem) was tested in MIA PaCa-2 (KRAS G12C), Capan-2 (KRAS G12V) and SW1990 (KRAS G12D) pancreatic cancer xenograft models. In the Capan-2 model, combination of LY3214996 with Gem alone was statistically additive (p&lt;0.001) and resulted in 14% tumor regressions (%dT/C =-14). In the MIA PaCa-2 model, LY3214996 has shown dose-dependent single agent activity resulting in 7 out of 7 partial responses at 100 mpk QD. In the combination study, LY3214996 enhanced the efficacy of Nab-pac+Gem and demonstrated 42% tumor regression (%dT/C =-42), and combination effect was additive (p=0.008). Combination of LY3214996+Gem+Nab-pac resulted in 1 complete response (CR) out of 6 whereas Nab-pac+Gem resulted in only 1 partial response (PR) out of 6. In SW1990 model, combination efficacy of LY3214996 and Nab-pac+Gem was additive (p=0.011) and resulted in ~88% tumor growth inhibition (%dT/C=12). Our data suggest that the efficacy of Nab-pac+Gem based chemotherapy can be enhanced through specific inhibition of ERK1/2 kinase activity in KRAS mutant PDAC, and supports the clinical testing of this combination in the current Phase I JUAB (LY3214996) study in metastatic PDAC (NCT02857270).
Citation Format: Shripad V. Bhagwat, Wenjuan Wu, Baohui Zhao, Weihua Shen, Lisa Kindler, Jennifer Stephens, Jason Manro, William McMillen, Sajan Joseph, Sheng-Bin Peng, Ramon V. Tiu. Inhibition of ERK by LY3214996 augments nab-paclitaxel and gemcitabine combination chemotherapy efficacy in preclinical models of pancreatic cancer [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 1307.