# Pause a failed drug so the tumour becomes sensitive to it again

Source: https://onco.cc/ideas/idea-bio1-drug-holiday-resensitisation/  
OnCo record `idea-bio1-drug-holiday-resensitisation` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018): https://doi.org/10.1056/NEJMoa1713137

## Connected records

- cancers: [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- drugs: [Encorafenib](https://onco.cc/drugs/encorafenib/), [Osimertinib](https://onco.cc/drugs/osimertinib/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)

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