Targeting MAPK Pathway Alterations: The Development and Efficacy of LY3214996, a Novel ERK1/2 Inhibitor in Cancer Therapy

The RAS/MAPK pathway, often disrupted in about 30% of cancers, includes ERK1 and ERK2 as pivotal elements. The effectiveness of targeting this pathway is evident through BRAF and MEK inhibitors' success in treating BRAF V600E/K metastatic melanoma. However, resistance is a common issue due to pathway reactivation. LY3214996, a highly selective ERK1 and ERK2 inhibitor with an IC50 of 5 nM for both enzymes, has been developed to target multiple nodes in the pathway, potentially enhancing efficacy and managing resistance.

LY3214996 has shown to significantly inhibit the proliferation of tumor cells with MAPK pathway alterations, such as those with BRAF, NRAS, or KRAS mutations. In xenograft models, the drug effectively inhibits the PD biomarker phospho-p90RSK1, with the effects correlating with compound exposure and anti-tumor activities. The inhibitor has demonstrated comparable or superior anti-tumor activity to other ERK inhibitors in BRAF or RAS mutant cell lines and xenografts.

Oral administration of LY3214996 has led to significant inhibition of tumor growth in various cancer models, including melanoma, colorectal, lung, and pancreatic cancers, and has shown good tolerability. The drug also exhibits anti-tumor activity in a vemurafenib-resistant melanoma model, suggesting its potential for treating patients who have become resistant to BRAF therapies.

Importantly, LY3214996 can be combined with other investigational and approved agents, particularly in KRAS mutant models. The combination of LY3214996 with the CDK4/6 inhibitor abemaciclib has shown to be well tolerated and induced potent tumor growth inhibition or regression in multiple cancer models, including KRAS mutant colorectal and non-small cell lung cancers.

The study introduces the preclinical profile of LY3214996, a novel ERK1/2 inhibitor currently in Phase I clinical trials for patients with advanced and metastatic cancers.

The research was presented by Shripad V. Bhagwat and colleagues at the American Association for Cancer Research Annual Meeting in 2017.