SOS1 is the top structural DAMPER in KRAS-mutant lung cancer (z_dr=+4.18). Pre-registered prediction: SOS1 should be more CRISPR-essential in KRAS-mutant cell lines. Result: DENIED. KRAS-WT cells are actually more dependent on SOS1 (d=+0.52, p=0.29). But KRAS itself is strongly essential in KRAS-MT (d=-1.34, p=0.0002). Structural DAMPERs predict pharmacological vulnerability. Structural ANCHORs predict genetic essentiality. These are two different axes, and the distinction matters for drug discovery.
In EGFR-mutant LUAD: EGFR is a structural ANCHOR (z=-2.05), KRAS is near-zero. In KRAS-mutant LUAD (n=155, EGFR-WT only): EGFR returns to z=+0.012 -- nearly zero. The driver gene controls which protein becomes the network's organizing center. When you swap the driver, the structural roles swap with it. SOS1 is revealed as a RAS-activated DAMPER (z=+4.18 in KRAS-MT vs -0.19 in KRAS-WT), not a pan-LUAD signal.
EGFR is a structural DAMPER in colorectal cancer (z=+2.41) and a structural ANCHOR in EGFR-mutant lung cancer (z=-2.05). Complete structural inversion. Yet EGFR inhibitors kill cells equally well in both cancers (d=-0.028, p=0.91, 5/5 drugs). This pre-registered result establishes a new principle: two opposite structural positions can produce the same pharmacological output when Driver Addiction Override takes effect.
We have been running a pre-registered series on a single question: can a protein's structural position in a cancer signaling network predict whether a drug targeting it will kill cancer cells? Thirteen experiments across six cancer types, two assay platforms, and two network scales later -- the answer is more nuanced, and more structured, than we expected.
Four pre-registered experiments on a 16-protein NSCLC signaling network. ERK1 is the biggest structural coupling bottleneck -- but DepMap CRISPR screens show MYC is the most essential undrugged node. Structural coherence and cancer survival are orthogonal axes (Spearman r = -0.722, p = 0.0024). The drug development landscape targets nodes in the wrong structural tier.