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Preprint WatchStrongOctober 10th, 2026

Cancer-associated mutations reconfigure dynamical responses in EGFR kinase

Tulli, L.; Lodola, A.; Mulholland, A. J.; Oliveira, A. S. F.

Cancer-associated kinase domain mutations reconfigure allosteric communication networks linking the ATP pocket to the P-loop, C-helix and other functional motifs of EGFR

Strong contradiction

3 prior failures

Three or more documented clinical failures match this mechanism, or a Phase 3 efficacy failure is on record.

This preprint applies dynamical-nonequilibrium molecular dynamics to the EGFR kinase domain and reports previously uncharacterised communication networks linking the ATP pocket to the P-loop, C-helix and other functional motifs, with L858R and L858R plus T790M reconfiguring those networks relative to wild type. Claidex holds three EGFR failures: tak-186-mvc-101-egfr-cd3-cobra-solid-tumors-phase1-2-efficacy-failure, fpi-2107-egfr-cmet-nsclc-dosimetry-uptake-failure and bg-60366-egfr-cdac-nsclc-strategic-shutdown, spanning efficacy failure, translational mismatch and sponsor decision. None of the three was a kinase-occupancy failure, which bounds what this result can fix: allosteric insight informs inhibitor design but says nothing about the delivery, uptake and target-density problems that ended the T cell engager and radioligand programs. EGFR remains tractable at the kinase level while the attrition has moved to modality.

Abstract excerpt

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that plays a fundamental role in regulating cellular proliferation, survival, and differentiation. EGFR's kinase domain catalyses the autophosphorylation that drives downstream signalling and is a known hotspot for cancer-associated mutations. Such substitutions often enhance receptor activation, driving oncogenesis and therapeutic resistance, with major implications for prognosis and treatment choice; consequently, a detailed understanding of this domain's functional dynamics, and how mutations reshape them, is essential. Here, we apply dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations to probe how changes at the ATP-binding site are transmitted throughout the kinase domain, ultimately shaping the behaviour of distal regions in the wild-type protein and in two of the most clinically observed non-small cell lung cancer variants, L858R and L858R+T790M. D-NEMD reveals previously uncharacterised communication networks linking the ATP pocket to key functional motifs, including the P-loop, C-helix, hinge region, activation loop, and F-helix, showing the intricate allosteric connectivity within this domain. Notably, numerous cancer-related mutation sites, despite being distant from the ATP site, map onto or lie close to these communication pathways, indicating that D-NEMD simulations can identify functionally relevant allosteric positions and potential mutation sites in EGFR. Our simulations further reveal that the two variants rewire EGFR's internal signal propagation network in distinct ways: L858R diminishes the transmission of structural changes to distal regions of the C-lobe, whereas introducing T790M in addition to L858R partially restores wild-type-like behaviour through compensatory rerouting of early-stage dynamical pathways.

Matching Claidex post-mortems

3 of 3 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.