Article
Extended Data Fig. 10 | Rapid non-uniform adaptation to conformation-
specific KRAS(G12C) inhibition. Left, at baseline, KR AS(G12C) cycles between
its active (GTP-bound) and inactive (GDP-bound) conformations. Active
KR AS(G12C) engages effector signalling, which regulates a transcriptional
repertoire (that is, KRAS output) that is responsible for controlling various
cellular functions. Middle, shortly after exposure to G12Ci treatment,
KR AS(G12C) is trapped in its inactive state, and eventually the cancer cell
population is sequestered in a low-KR AS output state. These cells stop
proliferating and enter quiescence (G0). Right, over time, some cells undergo
cell death and others adapt to the G12Ci to reactivate KR AS transcriptional
output, bypassing drug-induced quiescence to resume proliferation.
Our model suggests that this occurs because cells with low-KR AS output
produce new KR AS(G12C) protein, which is not bound by the drug. Then,
upstream signals operating in distinct cancer cell subpopulations—such as
those mediated by EGFR or AURK A—maintain the new protein in its active,
drug-insensitive state. By comparison, in cells in which these upstream signals
are not active (or in cells in which these signals are pharmacologically
inactivated), the new KR AS(G12C) spends a longer time in its inactive
conformation, in which it can be bound by the drug and inhibited. This
multifactorial process gives rise to a non-uniform treatment response with
diverging effects across the cancer cell population.