KRAS G12C: Covalent Inhibitor Switch

KRAS Genotype

Acquired resistance (Y96D)

Therapy

Sotorasib-like dose 0 nM

Upstream RTK / GEF drive 0.35

Live Readouts

KRAS-GTP (active)

Drug-locked (off)

ERK signal

Net growth rate

+0.00/hr

How it works

KRAS is a molecular switch that cycles between an inactive GDP-bound state and an active, signalling GTP-bound state:

GEF (SOS1)         GAP / intrinsic
KRAS-GDP  --------------->  KRAS-GTP  ---------------> KRAS-GDP
 (off)     nucleotide          (on)      GTP hydrolysis    (off)
           exchange, rate k_on          rate k_off

Each molecule in the cloud is simulated as a stochastic two-state Markov switch: in every timestep dt, P(off→on) = 1−e^−k_on·dt and P(on→off) = 1−e^−k_off·dt. Active (GTP-bound) KRAS drives the RAF→MEK→ERK cascade, so the fraction ON tracks live ERK signal, and net tumour growth rate is modelled as proportional to (ERK signal − basal death rate).

G12C mutants expose a cryptic pocket next to the GDP-binding site only while GDP-bound — the mechanism sotorasib (AMG 510) exploits. Covalent inhibition follows two-step Kitz–Wilson kinetics:

E + I ⇌(Ki) E·I  --kinact-->  E–I (irreversible)
k_lock = kinact · [I] / (Ki + [I])

Once locked, a molecule can never re-enter the GTP-on state again — the population's "off" fraction only grows. Wild-type KRAS lacks the reactive cysteine, so raising the dose slider does nothing to it (exactly why this drug class is mutant-selective). Toggling the Y96D-style resistance mutation blocks the drug pocket, driving k_lock back toward zero and reproducing clinically observed treatment escape.

KRAS-GDP (off) KRAS-GTP (on, signalling) Drug-locked (irreversible)

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