Table 1.

Preclinical models of acquired ADC resistance

ADCCell modelDosing approachFold resistance vs. ParentalMechanism of resistance proposedReference
T-DM1KPL-4-T-DM1-RContinuous, with increasing dose∼1,000XHER2 reduction; MDR1 induction; EGFR and IGF1Rβ induction, altered signalingLewis Phillips (24)
T-DM1BT-474-M1-T-DM1-RContinuous, with increasing dose∼100XPTEN and IGF1Rβ reduction; DARPP32 induction; MRP4 RNA inductionLewis Phillips (24)
T-DM1361-TMCyclical, with constant high dose256XMRP1 induction, trafficking protein modulationLoganzo, et al. (27)
T-DM1JIMT1-TMCyclical, with constant high dose16XHER2 reduction; trafficking protein modulationLoganzo et al. (27)
T-DM1HCC1954-TM, BT-474-TMCyclical, with constant high dose>1,000X, ∼11XHER2 reductionLoganzo et al. (34)
T-DM1N87-TMCyclical, with constant high dose∼100XTrafficking or lysosomal defects; CAV1 overexpressedSung et al. (49)
T-DM1BT-474, NCI-N87, SK-OV-3, MDA-MB-361Continuous, with increasing dose>100 to >1,000XNot reportedLi et al. (30)
BVKarpas-RContinuous, at high dose655XCD30 downregulationChen et al. (26)
BVL428-RCyclical, with constant high dose8.7XMDR1 inductionChen et al. (26)
BVKarpas-299-35RContinuous, with increasing dose>1,000XCD30 downregulationLewis et al. (25)
BVL540cy-35RContinuous, with increasing dose>100XLow-level MDR1 inductionLewis et al. (25)
BVDEL-35RContinuous, with increasing dose>1,000 to >10,000XMDR1 inductionLewis et al. (25)
Anti–CD22-vc-MMAEBJAB.Luc-22R1; WSU-DLCL2-22R1In vivo xenograft; cyclical increasing doseNo response to 8–12 mg/kg αCD22-vc-MMAE in vivoMDR1 inductionYu et al. (29)
DM1/maytansine-containing ADCs786-0 with SLC46A3 shRNAshRNA transfection (no drug induction)n/aSLC46A3 knockdownHamblett et al. (57)
  • Abbreviations: T-DM1, trastuzumab emtansine [Kadcyla; anti–HER2-trastuzumab-MCC-DM1]; BV, brentuximab vedotin [Adcetris; anti–CD30-cAC10-vc-MMAE].