{"entity":{"id":"idea-bio1-evolutionary-double-bind","kind":"idea","name":"Design drug pairs where resisting one makes you vulnerable to the other","aka":[],"tldr":"Choose two treatments so that whatever the tumour does to escape the first, it becomes easier to kill with the second. The immune system is a good candidate partner.","summary":"An evolutionary double bind pairs therapies with opposing selection pressures. Examples with preclinical support include MAPK inhibition increasing antigen presentation (making escape via MAPK reactivation immune-visible) and antiandrogen resistance via lineage plasticity creating dependence on EZH2. The proposal is to make double-bind logic an explicit design criterion, with a mechanistic screen for pairs in which resistance to A upregulates the target of B.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["ezh2","braf"],"drugs":[],"companies":[],"institutions":[],"pathways":["ras-mapk","ar-signaling"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-resistance","b-combination-space"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Combinations selected for double-bind structure delay resistance in vivo more than combinations selected for additive cytotoxicity, at matched toxicity.","rationale":"Resistance is a phenotype shift; if the shift can be predicted, the second agent can be aimed at the shifted state. This reframes combination discovery from additive killing to evolutionary trap design.","test":"Screen resistant derivative panels for upregulated targetable dependencies, validate the top three pairs in immunocompetent models, and take one pair into a phase 1b with mandatory paired biopsies.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":5},"route":"/ideas/idea-bio1-evolutionary-double-bind/","neighbours":{"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}]}}