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Cancer cells can install pumps in their outer membrane that throw chemotherapy back out as fast as it comes in. The same pumps guard the gut, brain and bone marrow in healthy tissue, which is why blocking them failed as a strategy and why drug designers now choose payloads the pumps cannot grip.
ATP-binding cassette transporters, chiefly ABCB1 (P-glycoprotein/MDR1), ABCG2 (BCRP) and ABCC1 (MRP1), hydrolyse ATP to export hydrophobic drugs: taxanes, vinca alkaloids, anthracyclines, MMAE, DM1, several TKIs (ABCB1); SN-38, topotecan, mitoxantrone, methotrexate (ABCG2). They are constitutive in intestine, liver, kidney, the blood-brain barrier and stem cells (including leukaemia and cancer stem cells, the 'side population'), and are induced by EMT transcription factors, hypoxia, NRF2 (KEAP1-mutant tumours), and by drug exposure itself (ABCB1 amplification and promoter fusions in ovarian cancer after taxanes). Three generations of P-gp inhibitors (verapamil, valspodar, tariquidar) failed in phase 3 through pharmacokinetic interactions and lack of benefit. Modern responses: choose payloads that are poor substrates (DXd and exatecan are less affected than SN-38 and MMAE; PBD dimers; radionuclides are pump-independent), use ADCs to raise intracellular delivery, and exploit collateral sensitivity (pump-expressing cells are more sensitive to some agents). Efflux at the BBB limits CNS activity of most drugs; brain-penetrant TKIs are engineered to evade P-gp.
A nightclub bouncer who throws out anyone in a particular jacket. Sacking the bouncer (P-gp inhibitors) also emptied the club of the staff who kept the place safe (gut, brain, marrow). The fix was to change jackets: payloads the bouncer does not recognise.
Shares SN-38, Exatecan (and derivatives), DXd, Payload (ADC) and the tags mechanism, mechanics-atlas.
Shares MMAE, Enfortumab vedotin, HER2, Paclitaxel / nab-paclitaxel and the tags mechanism, mechanics-atlas.
Shares Cancer stem cells & phenotypic plasticity, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Acquired resistance to every therapy and the tags mechanism, mechanics-atlas.
Shares The blood-brain barrier & brain metastasis, Lorlatinib, ALK, HER2 and the tags mechanism, mechanics-atlas.
Shares Cancer stem cells & phenotypic plasticity, Resistance routes: how a blocked pathway comes back, Acquired resistance to every therapy, Antibody-drug conjugate (ADC) and the tags mechanism, mechanics-atlas.
Shares KEAP1-NRF2 antioxidant pathway, KRAS and the tags mechanism, mechanics-atlas.
Shares ALK, HER2, KRAS and the tags mechanism, mechanics-atlas.
Shares Lorlatinib, Resistance routes: how a blocked pathway comes back, ALK, Trastuzumab deruxtecan and the tags mechanism, mechanics-atlas.