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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine
Shripad V Bhagwat1, William T McMillen2, Shufen Cai2
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. bhagwat_shripad_v@lilly.com.
Abstract:
The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).
Insights
A new ERK inhibitor, LY3214996, shows promise in preclinical models of BRAF- and KRAS-mutant cancers. This potent inhibitor effectively reduces tumor growth and overcomes resistance, advancing to clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrations in the Extracellular signal-Regulated Kinase (ERK) pathway are implicated in approximately 30% of human cancers.
- While BRAF- and MEK-targeted therapies show initial efficacy, acquired resistance limits long-term responses.
- ERK pathway reactivation is a key mechanism of acquired resistance, highlighting ERK inhibition as a therapeutic strategy.
Purpose of the Study:
- To identify and characterize LY3214996, a novel, potent, and selective ERK inhibitor.
- To evaluate the preclinical activity of LY3214996 in various cancer models, including those with BRAF and KRAS mutations and acquired resistance.
- To assess the potential of LY3214996 as a monotherapy or in combination with other agents.
Main Methods:
- In vitro cell proliferation assays to assess sensitivity to LY3214996 based on ERK pathway aberrations.
- Pharmacodynamic assessment of phospho-p90RSK1 inhibition in cells and tumors following LY3214996 treatment.
- In vivo studies using xenograft models with ERK pathway alterations to evaluate tumor growth inhibition and regression.
- Combination studies with a pan-RAF inhibitor in KRAS-mutant colorectal cancer models.
Main Results:
- LY3214996 demonstrated potent and selective ERK inhibition, evidenced by reduced phospho-p90RSK1 levels.
- Sensitivity to LY3214996 correlated with ERK pathway aberrations in vitro.
- LY3214996 exhibited dose-dependent tumor growth inhibition and regression in xenograft models, including BRAF- and KRAS-mutant cancers.
- Significant tumor growth inhibition was achieved with sustained target inhibition (50% for 8-16 hours) as a single agent.
- Synergistic effects were observed when LY3214996 was combined with a pan-RAF inhibitor in KRAS-mutant colorectal cancer models.
- Antitumor activity was confirmed in BRAF-mutant models with acquired resistance, both in vitro and in vivo.
Conclusions:
- LY3214996 is a potent and selective ERK inhibitor with significant preclinical antitumor activity.
- The drug shows efficacy in BRAF- and KRAS-mutant cancers and models with acquired resistance.
- These findings support the advancement of LY3214996 into clinical development for cancer treatment.
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