Epithelial–mesenchymal transition & drug efflux
How a cancer cell changes shape to migrate and to shrug off drugs. Transcription factors like ZEB1 and SNAIL loosen the cell, switch on pumps that eject chemotherapy, and hide it from the immune system.
TGF-β, Wnt, Notch, hypoxia, and inflammation induce ZEB1/2, SNAIL, SLUG, TWIST, which repress E-cadherin and epithelial genes and induce vimentin, N-cadherin, and matrix proteases. EMT confers invasiveness, stemness, resistance to apoptosis, upregulated ABC efflux transporters (ABCB1/P-gp, ABCG2), and immune exclusion. Partial EMT states dominate in tumours. Clinically: the mesenchymal/claudin-low TNBC subtype, sarcomatoid carcinomas, and TKI resistance (EGFR NSCLC). No approved EMT drug; strategies include TGF-β blockade (bintrafusp failed), efflux-agnostic payloads, and targeting mesenchymal-state dependencies (GPX4, ferroptosis).
In one picture
A brick in a wall (epithelial cell) turning into a nomad: it lets go of its neighbours, packs pumps to spit out poison, and puts on camouflage. The wall-brick was easy to hit; the nomad is not.
Diagram
top- No approved direct EMT inhibitor
- Payloads with low efflux susceptibility (sac-TMT's belotecan derivative claims this) and radiation (efflux-independent)
- TGF-β pathway blockade (mostly failed so far)
- Ferroptosis inducers for mesenchymal-state cells (preclinical)
- Immune approaches to overcome exclusion (STING, radiation)