{"entity":{"id":"idea-bio1-stromal-resistance-blockade","kind":"idea","name":"Block the survival signals the tumour's neighbours provide","aka":[],"tldr":"Cancer cells can survive a drug because surrounding normal cells feed them growth signals. Blocking those signals could make existing drugs work better and longer.","summary":"Fibroblast- and macrophage-derived factors including HGF, FGFs and neuregulin rescue tumour cells from targeted therapy in co-culture and in vivo, an effect largely invisible in monoculture screens. Environment-mediated resistance argues for combining targeted agents with blockade of the specific rescuing ligand or its receptor, selected by profiling the tumour's own stroma rather than the tumour cells alone.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1713137"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["single-cell-spatial"],"targets":["met","fap","her3"],"drugs":["patritumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-resistance","b-tme-immunosuppression"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Stroma-directed ligand blockade added to targeted therapy deepens response in tumours whose stroma expresses the rescuing ligand, and stromal ligand expression predicts which patients benefit.","rationale":"The rescue phenomenon was demonstrated systematically in large co-culture screens; the clinical failure of some combination trials may reflect unselected populations rather than a wrong mechanism.","test":"Score stromal ligand expression on baseline biopsies from a completed combination trial to test the predictive hypothesis retrospectively before designing a selected prospective study.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":5},"route":"/ideas/idea-bio1-stromal-resistance-blockade/","neighbours":{"technology":[{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"}],"target":[{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"her3","kind":"target","name":"HER3","route":"/targets/her3/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"}],"drug":[{"id":"patritumab-deruxtecan","kind":"drug","name":"Patritumab deruxtecan","route":"/drugs/patritumab-deruxtecan/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}]}}