Outsmarting Resistance with Rhythm

March 18, 2026

38 min episode · 2 min read

Ben Zeskin

Episode

38 min

Read time

2 min

AI-Generated Summary

Published Mar 19, 2026

Key Takeaways

✓Deep Cyclic Inhibition Timing: Continuous MEK inhibitors lose efficacy because by 24 hours they worsen disease-associated signals. Immuneering's transcriptomic platform identified the precise window to shut down the MAP kinase pathway for several hours, then release it — restoring normal healthy cell signaling cadence while repeatedly ambushing tumor cells before resistance pathways can consolidate.
✓MEK as Resistance Chokepoint: Targeting MEK rather than upstream KRAS blocks a broader range of downstream resistance mutations. When KRAS is inhibited continuously, tumors amplify mutant copies or acquire RAF mutations to bypass treatment. MEK sits further downstream, narrowing the escape routes available to the tumor and making durable suppression more achievable across the roughly 50% of all cancers driven by the MAP kinase pathway.
✓Tolerability Enables Combination Therapy: Atabimetinib adds no grade-3 adverse events beyond those attributable to the chemotherapy partner in Phase 2a data. This tolerability profile — a direct result of restoring intermittent signaling to healthy cells — allows combinations that continuous MEK inhibitors cannot support, including a planned anti-PD-1 study with Regeneron's Libtayo in non-small cell lung cancer, with first patient dosing targeted for second-half 2025.
✓Pancreatic Cancer as Platform Proof Point: Because approximately 97% of pancreatic cancers are MAP kinase-driven, no genetic pre-screening is required for trial enrollment, accelerating patient access. Twelve-month overall survival of 64% versus a 35% standard-of-care benchmark — sustained consistently at 6, 9, and 12 months — provides a high-signal validation environment for the deep cyclic inhibition platform before expanding to colorectal, melanoma, AML, and breast cancer indications.
✓Informatics-Driven Molecule Design: Immuneering's platform analyzes gene expression and transcriptomic data to engineer the pharmacokinetic profile of the molecule itself, not just select existing compounds. Atabimetinib is novel composition-of-matter, with a US patent granted in summer 2024, and lessons from its development are now being applied to a preclinical pipeline of deep cyclic inhibitors targeting additional oncology pathways.

What It Covers

Immuneering CEO Ben Zeskind explains how the company's informatics-driven "deep cyclic inhibition" approach to MEK inhibition delivers intense daily pulses rather than continuous suppression, producing 64% twelve-month overall survival in first-line pancreatic cancer patients versus 35% on standard-of-care gemcitabine/nab-paclitaxel chemotherapy.

Key Questions Answered

•Deep Cyclic Inhibition Timing: Continuous MEK inhibitors lose efficacy because by 24 hours they worsen disease-associated signals. Immuneering's transcriptomic platform identified the precise window to shut down the MAP kinase pathway for several hours, then release it — restoring normal healthy cell signaling cadence while repeatedly ambushing tumor cells before resistance pathways can consolidate.
•MEK as Resistance Chokepoint: Targeting MEK rather than upstream KRAS blocks a broader range of downstream resistance mutations. When KRAS is inhibited continuously, tumors amplify mutant copies or acquire RAF mutations to bypass treatment. MEK sits further downstream, narrowing the escape routes available to the tumor and making durable suppression more achievable across the roughly 50% of all cancers driven by the MAP kinase pathway.
•Tolerability Enables Combination Therapy: Atabimetinib adds no grade-3 adverse events beyond those attributable to the chemotherapy partner in Phase 2a data. This tolerability profile — a direct result of restoring intermittent signaling to healthy cells — allows combinations that continuous MEK inhibitors cannot support, including a planned anti-PD-1 study with Regeneron's Libtayo in non-small cell lung cancer, with first patient dosing targeted for second-half 2025.
•Pancreatic Cancer as Platform Proof Point: Because approximately 97% of pancreatic cancers are MAP kinase-driven, no genetic pre-screening is required for trial enrollment, accelerating patient access. Twelve-month overall survival of 64% versus a 35% standard-of-care benchmark — sustained consistently at 6, 9, and 12 months — provides a high-signal validation environment for the deep cyclic inhibition platform before expanding to colorectal, melanoma, AML, and breast cancer indications.
•Informatics-Driven Molecule Design: Immuneering's platform analyzes gene expression and transcriptomic data to engineer the pharmacokinetic profile of the molecule itself, not just select existing compounds. Atabimetinib is novel composition-of-matter, with a US patent granted in summer 2024, and lessons from its development are now being applied to a preclinical pipeline of deep cyclic inhibitors targeting additional oncology pathways.

Notable Moment

A first-line pancreatic cancer patient entered the atabimetinib trial so debilitated she required family assistance to attend appointments. After treatment, both liver lesions became undetectable, she resumed driving independently, rejoined a neighborhood walking group, and gained substantial weight — illustrating quality-of-life recovery beyond tumor response metrics.

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