Abstract 5501: Vertical inhibition of the MAPK pathway with D3S-002, a potent and selective ERK1/2 inhibitor, to improve anti-tumor activity of and overcome resistance to KRAS G12C inhibitors
Authors: Zhang Jing , Lu Jingtao , Zheng Zhiqiang , Lu Jiang , Wang Allison , Wang Jia , Chen Janet , Rui Haopeng , Chen Cheng , Chen Zhi Jian 
Published: April 2023

While covalent KRAS G12C inhibitors have demonstrated encouraging clinical efficacy in patients with KRAS G12C mutation, the overall response rate and progression-free survival appear to be suboptimal. Achieving deeper and more durable responses in these patients remain as major challenges. Preclinical and clinical translation research highlights adaptive feedback reactivation of the RAS-RAF-MEK-ERK signaling cascade as key molecular mechanisms driving primary and acquired resistance to KRAS G12C inhibitors. Concurrent inhibition of KRAS G12C and downstream MAPK pathway is thus an attractive combination strategy to improve clinical outcomes for KRAS G12C-mutant population.

D3S-002 is a potent and selective kinase inhibitor targeting ERK1/2, the final node of the RAS-MAPK pathway and the central mediator of the feedback activation loop. To investigate the combination effect of D3S-002 with KRAS G12C inhibitor D3S-001, this study utilized multiple preclinical in vivo models including cancer cell line-derived xenograft (CDX) tumors that are sensitive to, or primarily resistant to KRAS G12C inhibitors, and patient-derived xenograft (PDX) tumors that have progressed on KRAS G12C inhibitor treatment in the clinic. In NCI-H358 NSCLC and SW837 CRC models that are sensitive to KRAS G12C inhibitor monotherapy, adding D3S-002 to D3S-001 or to D3S-001 and cetuximab doublet regimen led to faster, deeper, and more durable anti-tumor responses at dose levels that are well tolerated in mice with no body weight loss observed. In NCI-H2122 NSCLC model that is primarily resistant to KRAS G12C inhibitor alone, the addition of D3S-002 resulted in near complete tumor growth inhibition.

Furthermore, CR9537 PDX model was established from tumor biopsy of a CRC patient who had progressed on combination treatment of KRAS G12C inhibitor MRTX849 and a SHP2 inhibitor in a clinical trial. Next generation sequencing (NGS) analysis identified secondary KRAS Q61H mutation as an acquired resistance mechanism. In this PDX model, KRAS G12C inhibitor, D3S-001 or MRTX849, monotherapy only achieved approximately 50% tumor growth inhibition, highlighting the acquired resistant phenotype. Adding D3S-002 to D3S-001 or MRTX849 resulted in over 80% tumor growth inhibition and significantly prolonged survival, suggesting the combination treatment can be beneficial for KRAS G12C inhibitor pre-treated patient population.

Collectively, vertical inhibition by concurrently targeting KRAS G12C and ERK1/2 with respective inhibitor D3S-001 and D3S-002 demonstrated enhanced anti-tumor activity in NSCLC and CRC models with different sensitivity to KRAS G12C inhibitor monotherapy. These results provide a strong rationale for further investigation of the combination strategy of D3S-001 and D3S-002 in KRAS G12C-mutant solid tumors in the clinic.

Citation Format: Jing Zhang, Jingtao Lu, Zhiqiang Zheng, Jiang Lu, Allison Wang, Jia Wang, Janet Chen, Haopeng Rui, Cheng Chen, Zhi Jian Chen. Vertical inhibition of the MAPK pathway with D3S-002, a potent and selective ERK1/2 inhibitor, to improve anti-tumor activity of and overcome resistance to KRAS G12C inhibitors. [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 5501.