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Preprint WatchStrongOctober 10th, 2026

Single molecule Grb2 dynamics reveal spatiomechanical modulation of RTK signaling across length scales

Jain, K.; Thakar, D.; Parihar, K.; Lin, J. J.; Hayward, M.-K.; Musiime, M.; Lakins, J.; Hansen, S. D.; Radhakrishnan, R.; Groves, J. T.; Weaver, V. M.; Low-Nam, S. T.

Extracellular matrix stiffness potentiates ligand-mediated EGFR signalling through integrin adhesions that reshape the membrane and create receptor signalling hotspots

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 reports that extracellular matrix stiffness potentiates ligand-mediated EGFR signalling, with integrin adhesions reshaping the membrane to create EGFR signalling hotspots, and uses a computational model plus biochemical membrane perturbation to implicate membrane curvature and topography in integrin-EGFR crosstalk. 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. A mechanism in which signalling output depends on matrix mechanics and receptor clustering rather than on receptor abundance alone bears directly on the second of those, where uptake and dosimetry rather than target presence determined the outcome. Preclinical models built at non-physiological stiffness may overstate the signalling dependence a stroma-rich tumour actually has.

Abstract excerpt

Extracellular matrix (ECM)-mediated cell adhesion and tension regulate development and disease through crosstalk with Receptor Tyrosine Kinases (RTKs). RTKs stimulate proliferation, survival, and metabolic reprogramming via Ras/ERK and PI3K/Akt signaling. Emerging evidence identify the biophysical and biochemical integration of integrin-mediated adhesions with RTK signaling, however, the molecular mechanisms regulating this phenotype remain poorly understood. Here, we demonstrate that ECM stiffness potentiates ligand-mediated epidermal growth factor receptor (EGFR) signaling at scales ranging from the single adaptor protein, Grb2 upward to multicellular spheroids and tissues. We show that ECM stiffness-driven RTK signaling is mediated by integrin adhesions that reshape the membrane to induce the formation of RTK signaling hotspots distributed globally across the cell membrane. A parsimonious computational model and biochemical membrane perturbations causally implicate membrane curvature and topography in tension-dependent integrin-EGFR crosstalk. The results demonstrate how the mechanical properties of the ECM direct molecular recruitment and confinement of signaling molecules to regulate growth factor-dependent RTK signaling. Given that many RTK-driven solid tumors develop a stiff stroma, the findings could explain why many therapeutic tyrosine kinase inhibitors develop clinical resistance. The findings suggest clarifying how tension regulates transmembrane receptor signaling could identify unique force-dependent molecular regulators towards which new antitumor therapies could be applied.

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.