# Efflux-agnostic therapy for mesenchymal TNBC

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

## TL;DR

Some tumours pump out every drug. Use treatments the pumps cannot touch: radiation, radioligands, immune cells, and payloads designed to evade them.

## Summary

Some tumours pump out every drug, so this idea treats mesenchymal or claudin-low TNBC and post-chemotherapy residual disease with modalities the pumps cannot touch: radiation, radioligands, T-cell engagers and ADCs whose payloads are not efflux substrates. Tumours with high ABCB1 or ABCG2 are expected to gain less from TOP1 or tubulin ADCs, since MMAE, DXd and SN-38 are all substrates, and more from radioimmunotherapy, engagers, degrader-antibody conjugates or sacituzumab tirumotecan. The test runs a retrospective ABCB1 and ABCG2 analysis of ASCENT and TROPION-Breast02 samples, prospective stratification in a TNBC ADC trial and payload comparisons in ABCG2-high PDX models. With preclinical evidence, it bears on the ADC technology and the efflux pump record.

## Fields

- Kind: Idea
- Last checked: 2026-09-04
- Hypothesis: Tumours with high ABC transporter expression (RNA or IHC) derive less benefit from TOP1/tubulin ADCs and more from radioligand therapy, T-cell engagers, or ADCs with non-substrate payloads.
- Rationale: Radiation and immune killing are not pumped out; sac-TMT's payload is reported to be a weaker efflux substrate; degrader payloads may also evade pumps.
- Proposed test: Retrospective ABCB1/ABCG2 analysis in ASCENT and TROPION-Breast02 samples; prospective stratification in a TNBC ADC trial; preclinical head-to-head of payloads in ABCG2-high PDX models.
- Maturity: preclinical-evidence

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Degrader-antibody conjugate (DAC)](https://onco.cc/technologies/degrader-antibody-conjugate/), [Radio-antibody & radio-ADC](https://onco.cc/technologies/radioimmunotherapy/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- drugs: [Sacituzumab tirumotecan](https://onco.cc/drugs/sacituzumab-tirumotecan/)
- pathways: [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/)
- terms: [Drug efflux pumps (ABC transporters)](https://onco.cc/terms/efflux-pump/)
- key papers: [Sacituzumab tirumotecan in previously treated metastatic triple-negative breast cancer: a randomized phase 3 trial](https://onco.cc/key-papers/paper-nct05347134-nat-med-2025/)

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