{"entity":{"id":"idea-bio1-drug-holiday-resensitisation","kind":"idea","name":"Pause a failed drug so the tumour becomes sensitive to it again","aka":[],"tldr":"Resistant cancer cells can become dependent on the drug they resisted, as shown for BRAF-inhibitor-resistant melanoma in mice. Stopping the drug for a defined washout and then rechallenging, while tracking the resistance allele in blood tumour DNA, could make the tumour vulnerable to it once more.","summary":"Drug addiction has been demonstrated for BRAF-inhibitor-resistant melanoma in mice and reported anecdotally in patients rechallenged after a break. Intermittent dosing prevented resistance in those models. A prospective trial would formalise rechallenge: after progression and a defined washout with an intervening therapy, patients are rechallenged with the original agent and monitored with ctDNA for the resistance allele's decline during the holiday.","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":["melanoma","nsclc"],"sections":[],"technologies":["liquid-biopsy"],"targets":[],"drugs":["encorafenib","osimertinib"],"companies":[],"institutions":[],"pathways":[],"terms":["resistance"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-tumor-heterogeneity"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"The resistant clone fraction measured in plasma falls during a drug holiday, and rechallenge after a defined interval produces objective responses in a clinically meaningful minority of patients.","rationale":"The fitness cost of resistance mutations is a general evolutionary principle and is directly measurable in plasma, which makes the holiday duration optimisable rather than arbitrary.","test":"Phase 2 rechallenge study with serial ctDNA during the holiday in BRAF-mutant melanoma or EGFR-mutant lung cancer; endpoints response rate on rechallenge and correlation with clone decay kinetics.","maturity":"early-clinical","actor":"clinic","cost":"medium","horizonYears":4},"route":"/ideas/idea-bio1-drug-holiday-resensitisation/","neighbours":{"cancer":[{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"drug":[{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}]}}