In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6 Resistance Mechanisms

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• Targeting cyclin-dependent kinases 4/6 (CDK4/6) combined with BRAF or MEK inhibitors is a therapeutic strategy for melanoma.
• Continuous dosing of CDK4/6 inhibitors can cause significant toxicities in patients.

Purpose of the Study:

• To optimize combination therapy schedules for MEK inhibitors (MEKi) and CDK4/6 inhibitors (CDK4/6i) in melanoma.
• To investigate resistance mechanisms to combined MEKi and CDK4/6i therapy.
• To identify therapeutic strategies to overcome acquired resistance.

Main Methods:

• Utilized quantitative and temporal in vivo reporting models to assess different combination schedules.
• Analyzed melanoma biopsies for phospho-S6 protein levels in patients treated with CDK4/6i plus targeted inhibitors.
• Investigated the role of NRAS mutations in conferring resistance to combination therapy.

Main Results:

• An intermittent schedule of CDK4/6 inhibitor (CDK4/6i) with continuous MEK inhibitor (MEKi) demonstrated more complete tumor responses.
• Tumor resistance was associated with enhanced ribosomal S6 protein phosphorylation, correlating with patient sample data.
• Upregulation or mutation of NRAS was linked to resistance in both in vivo models and patient samples.

Conclusions:

• Optimized intermittent dosing of CDK4/6i with continuous MEKi can improve melanoma treatment outcomes.
• Enhanced mTOR pathway signaling, particularly via NRAS alterations, drives resistance to combined MEKi and CDK4/6i therapy.
• Targeting mTORC1/2 with inhibitors like AZD2014 presents a viable strategy to overcome resistance and improve drug regimens.