Abstract 4188: The ERK1/2 inhibitor, JSI-1187, demonstrates preclinical efficacy in tumor models with MAPK pathway mutations

The MAPK pathway, via RAS-RAF-MEK-ERK, is one of the most important pathways for relaying signals from cell surface receptors for cell survival, proliferation, and differentiation. Many mutations were identified in this pathway and intensely studied, resulting in a number of therapeutics for various cancers (for example, EGFR mutant inhibitors, BRAF V600 mutant inhibitors and MEK inhibitors). A common mechanism of resistance to these therapeutics has emerged to be the reactivation of ERK1/2, the terminal kinase in this pathway. Inhibition of ERK1/2 activity could therefore be instrumental in various mutations in the MAPK pathway, either as single therapy or in combination with other compounds. Through internal effort, we discovered a novel ERK1/2 small molecule inhibitor, JSI-1187, which reversibly inhibited ERK2 with a Ki of less than 1 nM. In anti-proliferation assays, JSI-1187 had IC50 of 37 NM in the BRAF V600E melanonma cell line A375 and 48 NM in the BRAF V600E CRC cell line COLO 205. For cell lines with KRAS mutations, JSI-1187 had anti-proliferation IC50 of 130 NM in the CRC cell line HCT116 and 150 NM in the NSCLC cell line Calu-6. Furthermore, JSI-1187 inhibited the phosphorylation of the ERK substrate RSK1 in these cell lines. We also tested JSI-1187 using mouse CDX models. JSI-1187 showed tumor growth inhibition in a dose dependent manner in the xenograft models of A375, COLO 205, HCT116, and Calu-6. In the COLO 205 model, JSI-1187 caused tumor regression at the dose of 20 mg/kg QD. In the Calu-6 model, BID and QD dosing schedules were compared, with the result that 10 mg/kg BID and 20 mg/kg QD inhibit xenograft tumor growth similarly. Moreover, in the HCT116 model, JSI-1187 concentrations in plasma and tumor were measured, as well as phopspho-RSK1 levels in tumor. A PK/PD correlation was observed. In addition to being tested alone, JSI-1187 was also tested in combination with the BRAF inhibitor dabrafenib in the COLO 205 xenograft model. JSI-1187 and dabrafenib demonstrated synergistic efficacy in tumor growth inhibition. In conclusion, JSI-1187 can be potentially used for treatment of cancer with MAPK pathway mutations. Citation Format: Ao Li, Shanzhong Jian, Xia Yuan, Fengge Song, Shengwei Yang, Chengyi Du, Yue Tao, Liucheng Wang, Mingming Pan, Penghui Dong, jiajun Zhou, Zhengkang Ge, Qinghong Zhu, Wenshan Hao, Wen Xu, Jintao Zhang, Qun Li, Shaohui Wang. The ERK1/2 inhibitor, JSI-1187, demonstrates preclinical efficacy in tumor models with M