Abstract 429: Efficacy of JSI-1187 or VIC-1911 in combination with KRAS G12C inhibitors for the treatment of KRAS G12C-mutated non-small cell lung cancer and colorectal cancer
Authors: Zhang Lei , Li Ao , Jian Shanzhong , Du Chengyi , Zhu Wan , Tao Yue , Wang Meiwei , Xu Wen , Hao Wenshan , Paradiso Linda , Myers Thomas , Koya Keizo , Zhang Jintao 
Published: April 2023

Abstract
KRAS is the predominantly mutated RAS isoform, accounting for 85% of RAS mutations in cancers. KRAS G12C mutation occurs in approximately 14% of lung adenocarcinomas and 3% of colorectal adenocarcinomas. Several drugs have been developed that inhibit the function of KRAS proteins with a “G12C” mutation. The response rate to these drugs in patients with KRAS G12C-mutated NSCLC is approximately 40%. Primary resistance to G12C inhibitors in these patients may be explained in part by a lack of dependency on KRAS signaling. Despite the clinical benefit observed in some patients treated with G12C inhibitors, acquired resistance to single-agent inhibitor therapy eventually develops in most patients. KRAS G12C-mutated NSCLC cell lines treated with G12C- specific inhibitor demonstrated reactivation of the down-stream MAPK pathway as a mechanism of acquired resistance. As a terminal kinase in this pathway, inhibition of ERK1/2 activity could potentially be instrumental in overcoming G12C inhibitor resistance. Moreover, aurora kinase A (AURKA) has been identified as necessary for cancer cell escape from G12C inhibitor-induced quiescence, which may be due to a stabilizing reaction between AURKA, KRAS G12C and the downstream effector CRAF. JSI-1187 is an oral reversible ERK1/2 inhibitor, and VIC-1911 is an oral selective AURKA inhibitor. To evaluate the effects of the concomitant inhibition of JSI-1187 or VIC-1911 with sotorasib, we assessed the response in 4 G12C-mutated cell lines, including two NSCLC and two CRC. Loewe synergy scores calculated showed values between 0.5 to 14.3 in these cell lines, which signified a synergistic effect of JSI-1187 or VIC-1911 combined with sotorasib. JSI-1187 or VIC-1911 combined with sotorasib or adagrasib demonstrated marked enhancement of the antitumor effect compared with single-agent treatment in a H2122 mouse xenograft model. Additionally, the antitumor growth effect of JSI-1187 and sotorasib was significantly better than the combination of the MEK inhibitor, trametinib, and sotorasib. Greater inhibition of tumor growth was also observed for the combination vs. monotherapy in H358 and SW837 CRC- bearing mouse models. Furthermore, KRAS G12C-mutated patient-derived xenografts were used to investigate a synergistic effect. Combined treatment with VIC-1911 and sotorasib demonstrated greater tumor growth inhibition than either monotherapy alone in a NSCLC PDX model. In addition, the combination of JSI-1187 and sotorasib demonstrated a significant increase in tumor growth inhibition in a CRC PDX model. Taken together, our preclinical studies suggest that the combination of an ERK inhibitor, JSI-1187, or an AURKA inhibitor, VIC-1911, may potentially overcome the primary resistance and prevent or delay the acquired resistance to G12C inhibitors.
Citation Format: Lei Zhang, Ao Li, Shanzhong Jian, Chengyi Du, Wan Zhu, Yue Tao, Meiwei Wang, Wen Xu, Wenshan Hao, Linda Paradiso, Thomas Myers, Keizo Koya, Jintao Zhang. Efficacy of JSI-1187 or VIC-1911 in combination with KRAS G12C inhibitors for the treatment of KRAS G12C-mutated non-small cell lung cancer and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 429.