In earlier posts, I laid out why KRAS mutations have been so challenging for drug development, with very few effective and available treatment options for most people.
In KRAS, EGFR, and Drugs, I walked through the structural reasons KRAS is hard to drug.
Targeted Colon Cancer Treatment Status covered how these mutations drive colon cancer and where targeted therapies stand today.
And in Pan-RAS Inhibitors: Mechanism and Efficacy, I looked at efforts to shut down RAS more broadly.

This piece takes a different angle: don’t fight KRAS head-on—jam its wiring downstream. That means the MAPK pathway, especially MEK and ERK.

Disclaimer:

I’m a biotech scientist and not a medical doctor. I’m writing as an enthusiastic researcher and patient advocate, so please do not take this as expert medical advice. This blog is in progress, and I’m still verifying the contents for accuracy. The information is up to date as of 10/22/25

The MAPK pathway: the relay that keeps growth signals moving

MAPK Pathway

Image credit: Fred the Oyster, Wikipedia.

At a high level: RAS → RAF → MEK → ERK → transcription.
When KRAS is mutated “on,” this relay pushes cells to proliferate and resist death signals. If you can’t hit KRAS cleanly, cutting power further down the chain can still stall the tumor.

Why the first wave of MEK inhibitors struggled

The chemistry worked; the biology pushed back.

  • Feedback reactivation. Shut off MEK and the cell cranks up RAF/RTKs/KRAS upstream to re-ignite ERK.
  • Resistance mutations. Tumors evolve MEK1/2 pocket changes (e.g., F53L, K57N, Q56P) and sometimes ERK mutations downstream that bypass MEK entirely.
  • Toxicity ceiling. MAPK signaling matters in normal tissue (skin, retina, GI). Chronic blockade → rash, diarrhea, fatigue, ocular effects; doses get trimmed just as tumors start to adapt.

That’s why trametinib, cobimetinib, binimetinib had brief single-agent wins and then needed combinations: MEK + EGFR, MEK + CDK4/6, MEK + PI3K—all attempts to box in escape routes.

Deep Cyclic Inhibitors: a different rhythm (Immuneering)

Immuneering (IMRX) rethinks the problem with what they call Deep Cyclic Inhibitors (DCIs). Instead of sitting on MEK 24/7 (and advertising to the cell that something’s wrong), DCIs deliver high-amplitude pulses of MEK inhibition—deep enough to collapse ERK signaling—then allow a brief, controlled release. Normal cells can recover; KRAS-addicted tumor cells, which need continuous MAPK drive, don’t bounce back as easily.

Atebimetinib, their oral once-daily DCI of MEK, is built to encode that rhythm pharmacokinetically (not by complicated dosing calendars). The aim: longer pathway suppression, less feedback rebound, better tolerability.

🧠 Technical Box — Continuous vs. Deep Cyclic MEK inhibition

Continuous (traditional) MEK inhibition
• Flat exposure; MEK/ERK off constantly
• Strong feedback (RAF/RTKs) and fast resistance emergence
• Higher steady toxicity in MAPK-dependent tissues

Deep Cyclic Inhibition (DCI)
• Pulsed, high-amplitude MEK suppression with short troughs
• Blunts compensatory loops; maintains downstream suppression longer
• “Recovery windows” improve tolerability without losing anti-tumor pressure

Visual sketch:

Continuous vs Deep Cyclic

Schematic comparison of exposure patterns and expected biology.

Early clinical traction is in pancreatic and lung cancers—two MAPK-addicted settings:

  • Immuneering–Lilly clinical supply: https://ir.immuneering.com/news-releases/news-release-details/immuneering-announces-clinical-supply-agreement-lilly-evaluate
  • Pancreatic combo data summary: https://www.targetedonc.com/view/encouraging-survival-safety-data-for-atebimetinib-combo-in-pancreatic-cancer
  • Survival data update: https://ir.immuneering.com/news-releases/news-release-details/immuneering-discuss-recently-announced-overall-survival-data
  • Trial record: NCT06208124

Colorectal cancer isn’t on that trial card yet, but the biology overlaps. External analyses peg a non-trivial probability of expansion to mCRC if safety/efficacy hold: https://www.pharmaceutical-technology.com/data-insights/imm-6-415-immuneering-metastatic-colorectal-cancer-likelihood-of-approval/

Where the rest of the field is

Class KRAS coverage Stage Examples What we’ve learned
MEK inhibitors All KRAS Phase 2+ Trametinib, Binimetinib Need combos (EGFR, CDK4/6, PI3K) to delay rebound; monotherapy durability limited
ERK inhibitors All KRAS Phase 1/2 Ulixertinib One step further downstream; manageable tox so far; still early
Combo logic All KRAS Ongoing MEK+EGFR, MEK+CDK4/6, MEK+PI3K Best for cutting off feedback and cell-cycle escape; tolerability is the constraint

Academic groups (MD Anderson, Dana-Farber, others) are mapping synthetic-lethal pairs to pin KRAS-addicted cells without clobbering normal tissue.

Side effects: the practical limiter

Even with better scheduling, MEK/ERK drugs have familiar liabilities: rash/dermatitis, diarrhea, fatigue, retinal effects (rare cardiotoxicity).
DCIs try to lower the toxicity “area under the curve” while keeping the tumor under pressure. If the window holds, long-term use becomes realistic instead of a sprint to dose reduction.

What this could mean for colon cancer

Direct KRAS drugs (sotorasib, adagrasib) help G12C, which is a minority in CRC. The common G12D/G13D set still leans heavily on MAPK, which makes MEK/ERK the logical flank. Between the pan-RAS inhibitors and the MEK inhibitors, I’m very hopeful we can treat the nasty KRAS mutations that are pervasive in cancer in a more effective way. I know several people who have currently untreatable cancers due to different KRAS mutations, and these drugs provide some hope for the future.

If Immuneering’s readouts continue to trend in the right direction, Phase 3 around 2026–2027 and first pivotal readouts ~2028 are plausible.
For CRC specifically, assuming expansion, meaningful access in the early 2030s is a reasonable (and optimistic) line of sight. Not a silver bullet—more like another gear to mesh with EGFR/chemotherapy backbones and, eventually, smarter KRAS-variant-specific agents.

References and attributions

Personal note: this is still a moving target. The idea isn’t to crown MEK inhibition—the idea is to make it livable and keep the pathway cornered long enough to matter, especially for KRAS variants where the direct shots still aren’t there.